4-(1-(sulfonyl)-1h-indol-2-yl)-4-(hydroxy)-cyclohexa-2,5-dienone compounds and analogs thereof as therapeutic agents

ABSTRACT

This invention pertains to certain 4-(1-(sulfonyl)-1H-indol-2-yl)-4-(hydroxy)-cyclohexa-2,5-dienone compounds, and analogs thereof, including compounds of the following formula, which are, inter alia, antiproliferative agents, anticancer agents, and/or thioredoxin/thioredoxin reductase inhibitors: formula (I) wherein: Ar is a 1-(sulfonyl)-1H-indol-2-yl group; the bond marked α is independently: (a) a single bond; or: (b) a double bond; the bond marked β is independently: (a) a single bond; or: (b) a double bond; the group —OR O  is independently: (a) —OH; (b) an ether group (e.g., —OMe); or: (c) an acyloxy (i.e., reverse ester) group (e.g., —OC(═O)Me); each of R 2 , R 3 , R 5 , and R 6 , is independently a ring substituent and is: (a) H; (b) a monovalent monodentate substituent; or: (c) a ring substituent which, together with an adjacent ring substituent, and together with the ring atoms to which these ring substituents are attached, form a fused ring; and pharmaceutically acceptable salts, esters, amides, solvates, hydrates, and protected forms thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, for example, in the treatment of proliferative conditions, (e.g., cancer), and/or conditions mediated by thioredoxin/thioredoxin reductase.

TECHNICAL FIELD

This invention pertains generally to the field of therapeutic agents,and more specifically to certain4(1-(sulfonyl)-1H-indol-2-yl)4-(hydroxy)-cyclohexa-2,5-dienonecompounds, and analogs thereof, which are, inter alia, antiproliferativeagents, anticancer agents, and/or thioredoxin/thioredoxin reductaseinhibitors. The present invention also pertains to compositionscomprising such compounds, and the use of such compounds andcompositions, both in vitro and in vivo, for example, in the treatmentof proliferative conditions, cancer, and/or conditions mediated bythioredoxin/thioredoxin reductase.

BACKGROUND

Throughout this specification, including the claims which follow, unlessthe context requires otherwise, the word “comprise,” and variations suchas “comprises” and “comprising,” will be understood to imply theinclusion of a stated integer or step or group of integers or steps butnot the exclusion of any other integer or step or group of integers orsteps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

Ranges are often expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by the use of the antecedent “about,” itwill be understood that the particular value forms another embodiments.

Phenolic xenobiotics can be modified by cellular systems in a number ofways, e.g., oxidation, glucuronidation, sulphation, methylation,acetylation, etc., and the instability of certain phenolic proteintyrosine kinase (PTK) inhibitors has been documented. For example, theantitumor PTK inhibitor erbstatin, shown below, is known to have a shorthalf-life (<30 min) in fetal calf serum (see, e.g., Umezawa et al.,1991), and the lack of correlation between the activity of tyrphostins,shown below, against isolated enzymes and their effects in vitro and invivo, is noteworthy (see, e.g., Rambas et al., 1994). Di- andtri-phenolic tyrphostins decompose in solution to more active PTKinhibitors (see, e.g., Faaland et al., 1991), whereas tyrphostins devoidof hydroxy groups have a rapid onset of cellular activity (see, e.g.,Reddy et al., 1992), implicating metabolic oxidation to a quinone (orother) moiety as a possible bioactivating step.

Wells et al., 2000, describe several benzothiazole substituted quinolderivatives, shown below, where R¹ is —Ac, -Me, -Et, -nPr, or —CH₂C≡CH,and R² is -Me or -Et. These compounds were reported to have activityagainst certain colon (HCT-116 and HT29) and breast (MCF-7 and MDA468)cancer cell lines in vitro. Note that there is no mention of possibleapplication as thioredoxin/thioredoxin reductase inhibitors.

Stevens et al., 2003, describe various 4-aryl quinols and analogsthereof, including 4-(1H-indol-2-yl)quinols (see page 20 therein),wherein the 1H-indol-2-yl group bears an optional N-substituent (i.e.,1-substituent), denoted R^(N), which is —H. C₁₋₇alkyl,C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl (see page 22 therein). Nowhere in thisdocument is there any teaching or suggestion of a 1-sulfonyl substituenton the 1H-indol-2-yl group (e.g., as R^(N)).

Two compounds that contain a hydroxycyclohexadienone structure and whichapparently have antitumor activity have been reported: a hydroxylatedflavone-substituted quinol (i.e., a chromone substituted quinol) (see,e.g., Wada et al., 1987) and an oxidized estrone (see, e.g., Milic etal., 1999).

Several related antitumor epoxyquinols, such as Manumycin A (see, e.g.,Alcaraz et al., 1998) and LL-C 10037α (see, e.g., Wipf et al., 1994) areknown.

SUMMARY OF THE INVENTION

One aspect of the invention pertains to novel active compounds asdescribed herein.

Another aspect of the invention pertains to a composition comprising anactive compound as described herein and a pharmaceutically acceptablecarrier or diluent.

Another aspect of the invention pertains to an active compound asdescribed herein for use in a method of treatment of the human or animalbody.

Another aspect of the invention pertains to use of an active compound asdescribed herein for the manufacture of a medicament for use in thetreatment of, for example, a proliferative condition (e.g., cancer), acondition mediated by thioredoxin/thioredoxin reductase, etc.

Another aspect of the invention pertains to a method of inhibitingthioredoxin/thioredoxin reductase, in vitro or in vivo, comprisingcontacting a cell with an effective amount of an active compound asdescribed herein.

Another aspect of the invention pertains to a method of regulating cellproliferation, in vitro or in vivo, comprising contacting a cell with aneffective amount of an active compound as described herein.

Another aspect of the invention pertains to a method of (a) inhibitingcell proliferation; (b) inhibiting cell cycle progression; (c) promotingapoptosis; or (d) a combination of one or more of these, in vitro or invivo, comprising contacting a cell with an effective amount of acompound as described herein.

Another aspect of the invention pertains to a method for the treatmentof, for example, a proliferative condition (e.g., cancer), a conditionmediated by thioredoxin/thioredoxin reductase, etc., comprisingadministering to a subject suffering from said condition atherapeutically-effective amount of an active compound, as describedherein.

Another aspect of the present invention pertains to a kit comprising (a)the active compound, preferably provided as a pharmaceutical compositionand in a suitable container and/or with suitable packaging; and (b)instructions for use, for example, written instructions on how toadminister the active compound.

Another aspect of the present invention pertains to compounds obtainableby a method of synthesis as described herein, or a method comprising amethod of synthesis as described herein.

Another aspect of the present invention pertains to compounds obtainedby a method of synthesis as described herein, or a method comprising amethod of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates,as described herein, which are suitable for use in the methods ofsynthesis described herein.

Another aspect of the present invention pertains to the use of suchnovel intermediates, as described herein, in the methods of synthesisdescribed herein.

As will be appreciated by one of skill in the art, features andpreferred embodiments of one aspect of the invention will also pertainto other aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION Compounds

One aspect of the present invention pertains compounds having thefollowing formula:

wherein:

Ar is a 1-(sulfonyl)-1H-indol-2-yl group;

the bond marked α is independently:

-   -   (a) a single bond; or:    -   (b) a double bond;

the bond marked β is independently:

-   -   (a) a single bond; or:    -   (b) a double bond;

the group —OR^(O) is independently:

-   -   (a) —OH;    -   (b) an ether group (e.g., —OMe); or:    -   (c) an acyloxy (i.e., reverse ester) group (e.g., —OC(═O)Me);

each of R², R³, R⁵, and R⁶, is independently a ring substituent and is:

-   -   (a) H;    -   (b) a monovalent monodentate substituent; or:    -   (c) a ring substituent which, together with an adjacent ring        substituent, and together with the ring atoms to which these        ring substituents are attached, form a fused ring;    -   and pharmaceutically acceptable salts, esters, amides, solvates,        hydrates, and protected forms thereof.

Optical Isomers

Note that, in these compounds, one, two, or three of the ring atoms(marked with an asterisk (*) in the following formula) may be chiral(for example, depending on the bonds α and β, and the substituents, R²,R³, R⁵ and R⁶) and if so, may be in R or S configuration. Unlessotherwise specified, the resulting optical isomers (discussed below) areencompassed by the corresponding structure, which is silent as toconfiguration.

The Bonds, α and β

The bond marked α is independently a single bond or a double bond.

The bond marked β is independently a single bond or a double bond.

In one embodiment:

(a) α is independently a double bond and β is independently a doublebond; or:

(b) α is independently a single bond and β is independently a singlebond.

In one embodiment, α is independently a double bond and β isindependently a double bond (and the compound is substitutedcyclohexa-2,5-dienone):

In one embodiment, α is independently a single bond and β isindependently a single bond (and the compound is substitutedcyclohexan-2-one):

In one embodiment, α is independently a single bond and β isindependently a double bond (and the compound is substitutedcyclohex-2-enone):

Note that, in the context of α and β, a “double” bond includes both asimple double bond, such as the double bond in cyclohexene, and anaromatic “double” bond, such as, for example, the carbon-carbon bonds inbenzene.

Quinol Ring Substituents, R², R³, R⁵, and R⁶

The ring substituents, R², R³, R⁵, and R⁶, may be selected to improvethe physical or biological properties of the compound, for example, toimprove water solubility and/or bioavailability.

In one embodiment, each of R², R³, R⁵, and R⁶, is independently a ringsubstituent and is:

(a) H; or:

(b) a monovalent monodentate substituent (for example, as describedbelow under the heading “Quinol Ring Substituents: MonovalentMonodentate Substituents”); or:

(c) a ring substituent which, together with an adjacent ringsubstituent, and together with the ring atoms to which these ringsubstituents are attached, form a fused ring (for example, as describedbelow under the heading “Quinol Ring Substituents: Fused Rings”).

Quinol Ring Substituents: Monovalent Monodentate Substituents

In one embodiment, said monovalent monodentate substituent (e.g.,mentioned above in reference to R², R³, R⁵, and R⁶) is independently asdefined below for R^(P), or a thiol or thioether group (for example, asdescribed below under the heading “Quinol Ring Substituents: Thiols andThioethers”).

In one embodiment, said monovalent monodentate substituent isindependently selected from:

-   -   hydroxy (—OH);    -   halo;    -   azido;    -   C₁₋₇alkyl, including, e.g.,        -   halo-C₁₋₇alkyl;        -   amino-C₁₋₇alkyl (e.g., —(CH₂)_(w)-amino);        -   carboxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—COOH);        -   hydroxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—OH);        -   C₅₋₂₀aryl-C₁₋₇alkyl;    -   ether, including, e.g.,        -   C₁₋₇alkoxy;        -   halo-C₁₋₇alkoxy;        -   amino-C₁₋₇alkoxy (e.g., —O(CH₂)_(w)-amino);        -   carboxy-C₁₋₇alkoxy (e.g., —O(CH₂)_(w)—COOH);        -   hydroxy-C₁₋₇alkoxy (e.g., —O(CH₂)_(w)—OH);        -   C₅₋₂₀aryl-C₁₋₇alkoxy;    -   acyl, including, e.g.,        -   C₁₋₇alkyl-acyl;        -   halo-C₁₋₇alkyl-acyl;        -   amino-C₁₋₇alkyl-acyl (e.g., —C(═O)(CH₂)_(w)-amino);        -   carboxy-C₁₋₇alkyl-acyl (e.g., —C(═O)(CH₂)_(w)—COOH);        -   hydroxy-C₁₋₇alkyl-acyl (e.g., —C(═O)(CH₂)_(w)—OH);        -   C₅₋₂₀aryl-C₁₋₇alkyl-acyl;        -   C₅₋₂₀aryl-acyl; and    -   thiol (—SH);    -   thioether;    -   wherein w is an integer from 1 to 7, preferably 1 to 4,        preferably 1, 2, or 3.

In one embodiment, said monovalent monodentate substituent isindependently selected from:

-   -   —OH;    -   —F, —Cl, —Br, —I;    -   —N₃;    -   -Me, -Et, -nPr, -iPr, -tBu;    -   —OMe, —OEt, —O-nPr, —O-iPr, —O-tBu;    -   —C(═O)Me, —C(═O)Et, —C(═O)nPr, —C(═O)iPr, —C(═O)tBu, —C(═O)Ph,        —C(═O)Bn;    -   —SH;    -   —SMe, —SEt, —SnPr, —S-iPr, —S-nBu, —S-iBu, —S-sBu, —S-tBu,        —S—CH₂-Ph, —S-Ph;    -   a thioether group derived from cysteine, homocysteine,        glutathione, or a peptide of the type -Cys-(X)_(y)-Cys-, where X        is an amino acid, and y is an integer from 1 to 6.

In one embodiment, said monovalent monodentate substituent isindependently selected from: hydroxy, halo, C₁₋₇alkoxy, thiol, andthioether.

In one embodiment, said monovalent monodentate substituent isindependently selected from:

-   -   —OH;    -   —F, —Cl, —Br, —I;    -   —OMe, —OEt, —O-nPr, —O-iPr, —O-tBu;    -   —SH;    -   —SMe, —SEt, —SnPr, —S-iPr, —S-nBu, —S-iBu, —S-sBu, —S-tBu,        —S—CH₂-Ph, —S-Ph;    -   a thioether group derived from cysteine, homocysteine,        glutathione, or a peptide of the type -Cys-(X)_(y)-Cys-, where X        is an amino acid, and y is an integer from 1 to 6.

In one embodiment, said monovalent monodentate substituent isindependently selected from: halo, thiol, and thioether.

In one embodiment, said monovalent monodentate substituent isindependently selected from:

-   -   —F, —Cl, —Br, —I;    -   —SH;    -   —SMe, —SEt, —SnPr, —S-iPr, —S-nBu, —S-iBu, —S-sBu, —S-tBu,        —S—CH₂-Ph, —S-Ph;    -   a thioether group derived from cysteine, homocysteine,        glutathione, or a peptide of the type -Cys-(X)_(y)-Cys-, where X        is an amino acid, and y is an integer from 1 to 6.

Quinol Ring Substituents: Thiols and Thioethers

In one embodiment, one or more of said monovalent monodentatesubstituent(s), R², R³, R⁵, and R⁶, is a thiol (—SH) or a thioethergroup.

In one embodiment, if: α is a double bond and β is a double bond, then:thiols and thioethers are excluded from the alternatives for saidmonovalent monodentate substituents, R², R³, R⁵, and R⁶.

In one embodiment, one or both of R³ and R⁵, is a thiol or thioethergroup.

In one embodiment, exactly one of R³ and R⁵, is a thiol or thioethergroup.

In one embodiment, each of R³ and R⁵ is a thiol or thioether group.

In one embodiment, if: one or both of R³ and R⁵ is a thiol or thioethergroup; then: α is a single bond; and β is a single bond.

In one embodiment, if: R³ is a thiol or thioether group; then: β is asingle bond.

In one embodiment, if: R⁵ is a thiol or thioether group; then: α is asingle bond.

In one embodiment, if: each of R³ and R⁵ is a thiol or thioether group;then: α is a single bond; and β is a single bond.

In one embodiment, α is a single bond, β is a single bond, and: one ormore of said monovalent monodentate substituent, R², R³, R⁵, and R⁶, isa thiol or a thioether group.

In one embodiment, α is a single bond, β is a single bond, and: one orboth of R³ and R⁵ is a thiol or thioether group.

In one embodiment, α is a single bond, β is a single bond, and: exactlyone of R³ and R⁵is a thiol or thioether group.

In one embodiment, α is a single bond, β is a single bond, and: each ofR³ and R⁵ is a thiol or thioether group.

In one embodiment, α is a single bond, β is a single bond, and: each ofR³ and R⁵ is a thioether group, and: R³ and R⁵ are linked. For example,R³ and R⁵ may, together, form a part of a peptide comprising thesequence -Cys-(X)_(y)-Cys-, where X is an amino acid (e.g., α-aminoacid), and y is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), andthe —SH groups of the two cysteine residues are attached to thecyclohexa-2,5-dienone ring.

Such compounds may be considered to be mono- and di-thiol adducts of thecorrsponding cyclohex-2,5-dienone (see below).

In such cases, the thiol and thioether group may collectively be denoted—SR^(S).

In one embodiment, R^(S) is —H or an organic group (typically from 1 to30 atoms other than hydrogen) which optionally bears one or moresubstituents, such as hydroxy, carboxy, carboxylate, acyloxy, amino,amido, and acyl amido groups.

In one embodiment:

(a) R^(S) is —H, C₁₋₇alkyl (including, e.g., C₅₋₂₀aryl-C₁₋₇alkyl),C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl; and is optionally substituted; or

(b) —SR^(S) is a thioether group derived from a thiol-containing aminoacid or peptide.

In one embodiment:

(a) R^(S) is —H, C₁₋₇alkyl (including, e.g., C₅₋₂₀aryl-C₁₋₇alkyl) orC₅₋₂₀aryl; and is optionally substituted; or

(b) —SR^(S) is a thioether group derived from a thiol-containing aminoacid or peptide.

In one embodiment:

(a) R^(S) is —H, C₁₋₇alkyl (including, e.g., C₅₋₂₀aryl-C₁₋₇alkyl) orC₅₋₂₀aryl; and is optionally substituted.

In one embodiment:

(b) —SR^(S) is a thioether group derived from a thiol-containing aminoacid or peptide.

In one embodiment, —SR^(S) is a thioether group derived from athiol-containing compound, such as, for example, a thiol-containingamino acid, e.g., cysteine, homocysteine, etc., or a thiol-containingpeptide, e.g., a peptide comprising a thiol-containing amino acid, forexample, glutathione and peptides (e.g., comprising from 4 to 100,preferably from 4 to 20, more preferably 4 to 10, amino acids)comprising the sequence -Cys-(X)_(y)-Cys-, where X is an amino acid(e.g., α-amino acid), and y is an integer from 1 to 6 (e.g., 1, 2, 3, 4,5, or 6); as well as and esters (e.g., methyl esters) and amides (e.g.,acetic acid amides) thereof.

Some examples of such groups are shown below (where n is e.g., 1, 2, or3):

In one embodiment:

(a) R^(S) is selected from: —H, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu,-tBu, —CH₂-Ph, -Ph; or:

(b) —SR^(S) is a thioether group derived from cysteine, homocysteine,glutathione, or a peptide comprising the sequence -Cys-(X)_(y)-Cys-,where X is an amino acid, and y is an integer from 1 to 6.

The cyclohexa-2,5-dienone compounds described herein undergo additionreactions with thiols, to yield thiol mono- and/or di-adducts (see“Synthesis” below). Without wishing to be bound by any particulartheory, it is believed that the addition reaction is reversible, andthat such adducts may undergo elimination reaction, e.g., in vivo, toyield the original cyclohexa-2,5-dienone compound. In this way, thethiol mono- and/or di-adducts may act as prodrugs for the correspondingcyclohexa-2,5-dienone compounds; the thiol mono- and/or di-adducts mayalso have improved properties, e.g., water solubility, as compared tothe corresponding cyclohexa-2,5-dienone compounds.

Quinol Ring Substituents: No Fused Rings

In one embodiment, each of R², R³, R⁵, and R⁶, is independently a ringsubstituent and is:

(a) H; or:

(b) a monovalent monodentate substituent (for example, as describedbelow under the heading “Quinol Ring Substituents: MonovalentMonodentate Substituents”).

In one embodiment, R⁵ and R⁶ are —H; and α, β, R², R³, Ar, and R^(O) areas defined herein, but R² and R³ do not also form a fused ring:

In one embodiment, R² and R³ are —H; and α, β, R⁵, R⁶, Ar, and R^(O) areas defined herein, but R⁵ and R⁶ do not also form a fused ring:

In one embodiment, R² and R⁶ are —H; and α, β, R³, R⁵, Ar, and R^(O) areas defined herein:

In one embodiment, R³ and R⁵ are —H; and α, β, R², R⁶, Ar, and R^(O) areas defined herein:

In one embodiment, R², R³, R⁵ and R⁶ are —H; and α, β, Ar, and R^(O) areas defined herein:

In one embodiment, R², R³, R⁵ and R⁶ are —H; α is a double bond; β is adouble bond; and Ar and R^(O) are as defined herein:

In one embodiment, R², R³, R⁵ and R⁶ are —H; α is a single bond; β is asingle bond; and Ar and R^(O) are as defined herein:

In one embodiment, R², R³, R⁵ and R⁶ are —H; α is a single bond; β is adouble bond; and Ar and R^(O) are as defined herein:

Ring Substituents: Fused Rings

In one embodiment, one or more ring substituents (e.g., R³, R⁴, R⁵, orR⁶), together with an adjacent ring substituent (i.e., selected from theremainder of R³, R⁴, R⁵, and R⁶), and together with the ring atoms towhich these ring substituents are attached, form a fused ring (fused tothe main ring).

In one embodiment,

(a) R² and R³, together with the ring atoms to which they are attached,form a fused ring;

(b) R⁵ and R⁶, together with the ring atoms to which they are attached,form a fused ring; or:

(c) or both (a) and (b).

In one embodiment, the fused ring (or, if there are two fused rings, oneof them, or each of them) is a fused aromatic ring.

In one embodiment, the fused ring (or, if there are two fused rings, oneof them, or each of them) is a fused aromatic ring with 5 or 6 ringatoms.

In one embodiment, the fused ring (or, if there are two fused rings, oneof them, or each of them) is a fused aromatic ring with 6 ring atoms.

In one embodiment, the fused ring (or, if there are two fused rings, oneof them, or each of them) is a fused aromatic ring with 6 ring carbonatoms.

Where ring substituents, together with the ring atoms to which they areattached, form an aromatic ring (fused to the main ring), that ring mayitself be substituted with one or more aryl substituents, for example,as defined for R^(P).

In one embodiment, R² and R³, together with the ring atoms to which theyare attached, form a fused ring, as described above (e.g., a fusedaromatic ring; a fused aromatic ring with 5 or 6 ring atoms; a fusedaromatic ring with 6 ring atoms; a fused aromatic ring with 6 ringcarbon atoms).

In one embodiment, R² and R³form a fused benzene ring; β is a doublebond; and α, Ar, R^(O), R⁵, and R⁶ are as defined herein:

In a further embodiment, R⁵ and R⁶ do not also form a fused ring.

In one embodiment, R² and R³form a fused benzene ring; β is a doublebond; R⁵ is —H; and α, R⁶, Ar, and R^(O) are as defined herein:

In one embodiment, R² and R³ form a fused benzene ring; β is a doublebond; R⁶ is —H; and α, R⁵, Ar, and R^(O) are as defined herein:

In one embodiment, R² and R³form a fused benzene ring; β is a doublebond; R⁵ and R⁶ are —H; and α, Ar, and R^(O) are as defined herein:

In one embodiment, R² and R³ form a fused benzene ring; β is a doublebond; R⁵ and R⁶ are —H; α is a double bond; and Ar and R^(O) are asdefined herein:

In one embodiment, R⁵ and R⁶, together with the ring atoms to which theyare attached, form a fused ring, as described above (e.g., a fusedaromatic ring; a fused aromatic ring with 5 or 6 ring atoms; a fusedaromatic ring with 6 ring atoms; a fused aromatic ring with 6 ringcarbon atoms).

In one embodiment, R⁵ and R⁶ form a fused benzene ring; α is a doublebond; and β, R², R³, Ar, and R^(O) are as defined herein:

In a further embodiment, R² and R³ do not also form a fused ring.

In one embodiment, R⁵ and R⁶ form a fused benzene ring; α is a doublebond; R³ is —H; and β, R², Ar, and R^(O) are as defined herein:

In one embodiment, R⁵ and R⁶ form a fused benzene ring; α is a doublebond; R² is —H; and β, R³, Ar, and R^(O) are as defined herein:

Oxy Subsitutents, R^(O)

The oxy substituent, R^(O), is independently: (a) —H; or: (b) other than—H.

In one embodiment, the group —OR^(O) is independently:

(a) —OH;

(b) an ether group (e.g., —OMe); or

(c) an acyloxy (i.e., reverse ester) group (e.g., —OC(═O)Me);

In one embodiment, R^(O) is independently:

(a) —H;

(b) C₁₋₇alkyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl; and is optionallysubstituted; or

(c) C₁₋₇alkyl-acyl, C₃₋₂₀heterocyclyl-acyl, or C₅₋₂₀aryl-acyl; and isoptionally substituted.

In one embodiment, R^(O) is unsubstituted.

In one embodiment, R^(O) is substituted.

Oxy Subsitutent, R^(O), is —H

In one embodiment, R^(O) is independently —H.

In one embodiment, R^(O) is —H; and R², R³, R⁵, R⁶, α, β, and Ar are asdefined herein:

In one embodiment, R^(O) is —H; α is a double bond; β is a double bond;and R², R³, R⁵, R⁶, and Ar are as defined herein:

In one embodiment, R^(O) is —H; α is a single bond; β is a single bond;and R², R³, R⁵, R⁶, and Ar are as defined herein:

In one embodiment, R^(O) is —H; α is a single bond; β is a double bond;and R², R³, R⁵, R⁶, and Ar are as defined herein:

In one embodiment, R^(O) is —H; R², R³, R⁵ and R⁶ are —H; α is a doublebond; β is a double bond; and Ar is as defined herein:

In one embodiment, R^(O) is —H; R², R³, R⁵ and R⁶ are —H; α is a singlebond; β is a single bond; and Ar is as defined herein:

In one embodiment, R^(O) is —H; R², R³, R⁵ and R⁶ are —H; α is a singlebond; β is a double bond; and Ar is as defined herein:

In one embodiment, R^(O) is —H; R² and R³ form a fused benzene ring; R⁵and R⁶ are —H; α is a double bond; β is a double bond; and Ar is asdefined herein:

Oxy Substituent, R^(O), is Other Than —H

In one embodiment, R^(O) is independently other than —H.

Without wishing to be bound by any particular theory, it is believedthat the group —OR^(O) is converted (e.g.,hydrolyzed, metabolized, etc.)to give the group —OH, in vivo. Consequently, in one embodiment, thegroup —OR^(O) is selected to be readily hydrolyzed in vivo.

In one embodiment, the group —OR^(O) is independently:

(b) an ether group; or

(c) an acyloxy (i.e., reverse ester) group.

In one embodiment, the group —OR^(O) is independently (b).

In one embodiment, the group —OR^(O) is independently (c).

In one embodiment, R^(O) is independently:

(b) C₁₋₇alkyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl; and is optionallysubstituted;

(c) C₁₋₇alkyl-acyl, C₃₋₂₀heterocyclyl-acyl, or C₅₋₂₀aryl-acyl; and isoptionally substituted.

In one embodiment, the group —OR^(O) is independently (b).

In one embodiment, the group —OR^(O) is independently (c).

In one embodiment, R^(O) is unsubstituted.

In one embodiment, R^(O) is substituted.

In one embodiment, R^(O) is optionally substituted with one more of thefollowing groups:

-   -   hydroxy (—OH);    -   halo;    -   carboxy (—COOH);    -   amino; and,    -   C₅₋₂₀aryl.

In one embodiment, R^(O) is an amino-C₁₋₇alkyl-acyl group, of theformula —C(═O)-J-K, wherein J is a C₁₋₇alkylene group, and K is an aminogroup. In one embodiment, R^(O) is —C(═O)(CH₂)_(n)—K, where n is aninteger from 1 to 7, preferably 1 to 3, and K is an amino group. Forexample, in one embodiment, R^(O) is —C(═O)CH₂CH₂CH₂NH₂.

The Aryl Group, Ar

The aryl group, Ar, is a 1-(sulfonyl)-1H-indol-2-yl group.

In one embodiment, Ar is a group of the following formula:

wherein:

-   -   R^(SO) is independently a sulfonyl substituent; and each of        R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) is independently an        indolyl subsitutent.

The Sulfonyl Substituent, R^(SO)

In one embodiment, the sulfonyl substituent, R^(SO), is C₁₋₇alkyl,C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl; and is optionally substituted.

In one embodiment, R^(SO) is C₁₋₇alkyl or C₅₋₂₀aryl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₁₋₇alkyl; and is optionally substituted.

In one embodiment, R^(SO) is C₃₋₂₀heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₂₀aryl; and is optionally substituted.

In one embodiment, R^(SO) is unsubstituted.

In one embodiment, R^(SO) is substituted.

Examples of substituents are described below, for example, as definedfor R^(P).

The Sulfonyl Substituent, R^(SO): Alkyl Sulfonyl

In one embodiment, R^(SO) is C₁₋₇alkyl; and is optionally substituted.

In one embodiment, R^(SO) is C₁₋₆alkyl; and is optionally substituted.

In one embodiment, R^(SO) is C₁₋₅alkyl; and is optionally substituted.

In one embodiment, R^(SO) is C₁₋₄alkyl; and is optionally substituted.

In one embodiment, R^(SO) is C₁₋₃alkyl; and is optionally substituted.

In one embodiment, R^(SO) is methyl or ethyl; and is optionallysubstituted.

In one embodiment, R^(SO) is methyl; and is optionally substituted.

In one embodiment, R^(SO) is substituted.

In one embodiment, R^(SO) is unsubstituted.

Examples of substituents are described below, for example, as definedfor R^(P).

When R^(SO) is -Me, the sulfonyl group, —SO₂R^(SO), is “mesyl.”

When R^(SO) is —CF₃, the sulfonyl group, —SO₂R^(SO), is “triflyl.”

When R^(SO) is -Et, the sulfonyl group, —SO₂R^(SO), is “esyl.”

When R^(SO) is —C₄F₉, the sulfonyl group, —SO₂R^(SO), is “nonaflyl.”

When R^(SO) is —CH₂CF₃, the sulfonyl group, —SO₂R^(SO), is “tresyl.”

The Sulfonyl Substituent, R^(SO): Alkyl Sulfonyl: Substituents

In one embodiment, R^(SO) is C₁₋₇alkyl (or as defined above), optionallysubstituted with one more substituents as defined for R^(P).

In one embodiment, R^(SO) is C₁₋₇alkyl (or as defined above), optionallysubstituted with one more of the following groups:

-   -   hydroxy (—OH);    -   halo;    -   carboxy (—COOH);    -   amino; and,    -   C₅₋₂₀aryl.

In one embodiment, R^(SO) is selected from:

-   -   hydroxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—OH);    -   halo-C₁₋₇alkyl;    -   carboxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—COOH);    -   amino-C₁₋₇alkyl (e.g., —(CH₂)_(w)-amino); and,    -   C₅₋₂₀aryl-C₁₋₇alkyl;    -   wherein w is an integer from 1 to 7, preferably 1 to 4,        preferably 1, 2, or 3.

The Sulfonyl Substituent, R^(SO): Heterocyclyl Sulfonyl

In one embodiment, R^(SO) is C₃₋₂₀heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₂₀heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₁₅heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₁₂heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₁₀heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₉heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₇heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₆heterocyclyl; and is optionallysubstituted.

In one embodiment, R^(SO) is substituted.

In one embodiment, R^(SO) is unsubstituted.

Examples of substituents are described below, for example, as definedfor R^(P).

The Sulfonyl Substituent, R^(SO): Aryl Sulfonyl

In one embodiment, R^(SO) is C₅₋₂₀aryl; and is optionally substituted.

In one embodiment, R^(SO) is C₅₋₂₀carboaryl; and is optionallysubstituted.

In one embodiment, R^(SO) is C₅₋₁₀aryl; and is optionally substituted.

In one embodiment, R^(SO) is C₅₋₁₀carboryl; and is optionallysubstituted.

In one embodiment, R^(SO) is naphthyl or phenyl; and is optionallysubstituted.

In one embodiment, R^(SO) is naphthyl; and is optionally substituted.

In one embodiment, R^(SO) is C₅₋₆aryl; and is optionally substituted.

In one embodiment, R^(SO) is C₅₋₆carboaryl ; and is optionallysubstituted.

In one embodiment, R^(SO) is phenyl; and is optionally substituted.

In one embodiment, R^(SO) is unsubstituted.

In one embodiment, R^(SO) is substituted.

Examples of substituents are described below, for example, as definedfor R^(P).

The Sulfonyl Substituent, R^(SO): Phenyl Sulfonyl

In one embodiment, R^(SO) is (an optionally substituted phenyl group):

wherein p is an integer from 0 to 5, and each R^(P) is a phenylsubstituent.

In one embodiment, R^(SO) is an unsubstituted phenyl group.

In one embodiment, R^(SO) is a substituted phenyl group.

In one embodiment, p is 0, 1, 2, 3, 4 or 5.

In one embodiment, p is 0, 1, 2, 3, or 4.

In one embodiment, p is 0, 1, 2 or 3.

In one embodiment, p is 0, 1 or 2.

In one embodiment, p is 0 or 1.

In one embodiment, p is 1, 2, 3, 4 or 5.

In one embodiment, p is 1, 2, 3, or 4.

In one embodiment, p is 1, 2 or 3.

In one embodiment, p is 1 or 2.

In one embodiment, p is 0.

In one embodiment, p is 1.

In one embodiment, p is 2.

In one embodiment, p is 3.

In one embodiment, p is 4.

In one embodiment, p is 5.

If the phenyl group has less than the full complement of substituents,they may be arranged in any combination. For example, if the phenylgroup has a single substituent other than hydrogen, it may be in the 2-,3-, or 4-position. Similarly, if the phenyl group has two substituentsother than hydrogen, they may be in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or3,5-positions. If the phenyl group has three substituents other thanhydrogen, they may be in, for example, the 2,3,4-, 2,3,5-, 2,3,6-,2,4,5-, 2,5,6-, or 3,4,5-positions. If the phenyl group has foursubstituents other than hydrogen, they may be in, for example, the3,4,5,6-, 2,4,5,6-, 2,3,5,6-, 2,3,4,6-, or 2,3,4,5-positions.

In one embodiment, p is 3 and the R^(P) groups are in the 2-, 4-, and6-positions.

In one embodiment, p is 3 and the R^(P) groups are in the 3-, 4-, and5-positions.

In one embodiment, p is 2 and the R^(P) groups are in the 2- and4-positions.

In one embodiment, p is 2 and the R^(P) groups are in the 2- and5-positions.

In one embodiment, p is 2 and the R^(P) groups are in the 2- and6-positions.

In one embodiment, p is 2 and the R^(P) groups are in the 3- and4-positions.

In one embodiment, p is 2 and the R^(P) groups are in the 3- and5-positions.

In one embodiment, p is 1 and R^(P) is in the 2-, 3-, or 4-position.

In one embodiment, p is 1 and R^(P) is in the 2- or 4-position.

In one embodiment, p is 1 and R^(P) is in the 2-position.

In one embodiment, p is 1 and R^(P) is in the 3-position.

In one embodiment, p is 1 and R^(P) is in the 4-position.

Examples of substituents are described below.

When R^(SO) is -Ph, the sulfonyl group, —SO₂R^(SO), is “besyl.”

When R^(SO) is 4-Me, the sulfonyl group, —SO₂R^(SO), is “tosyl.”

When R^(SO) is 4-Cl, the sulfonyl group, —SO₂R^(SO), is “closyl.”

When R^(SO) is 4-Br, the sulfonyl group, —SO₂R^(SO), is “brosyl.”

When R^(SO) is 4-NO₂, the sulfonyl group, —SO₂R^(SO), is “nosyl.”

The Sulfonyl Substituent, R^(SO): Naphthyl Sulfonyl

In one embodiment, R^(SO) is (an optionally substituted naphth-1-ylgroup or naphth-2-yl group):

wherein q is an integer from 0 to 3; r is an integer from 0 to 4; andeach R^(P) is a naphthyl substituent.

In one embodiment, R^(SO) is an unsubstituted naphth-1-yl group ornaphth-2-yl group.

In one embodiment, R^(SO) is a substituted naphth-1-yl group ornaphth-2-yl group.

In one embodiment, R^(SO) is an optionally substituted naphth-1-ylgroup.

In one embodiment, R^(SO) is an unsubstituted naphth-1-yl group.

In one embodiment, R^(SO) is a substituted naphth-1-yl group.

In one embodiment, R^(SO) is an optionally substituted naphth-2-ylgroup.

In one embodiment, R^(SO) is an unsubstituted naphth-2-yl group.

In one embodiment, R^(SO) is a substituted naphth-2-yl group.

In one embodiment, q is 0, 1, 2 or 3.

In one embodiment, q is 0, 1 or 2.

In one embodiment, q is 0 or 1.

In one embodiment, q is 1, 2 or 3.

In one embodiment, q is 1 or 2.

In one embodiment, q is 0.

In one embodiment, q is 1.

In one embodiment, q is 2.

In one embodiment, q is 3.

In one embodiment, r is 0, 1, 2, 3, or 4.

In one embodiment, r is 0, 1, 2 or 3.

In one embodiment, r is 0, 1 or 2.

In one embodiment, r is 0 or 1.

In one embodiment, r is 1, 2, 3, or 4.

In one embodiment, r is 1, 2 or 3.

In one embodiment, r is 1 or 2.

In one embodiment, r is 0.

In one embodiment, r is 1.

In one embodiment, r is 2.

In one embodiment, r is 3.

In one embodiment, r is 4.

Examples of substituents are described below.

When R^(SO) is 5-dimethylaminonaphth-1-yl, the sulfonyl group,—SO₂R^(SO), is “dansyl.”

The Sulfonyl Substituent, R^(SO): Phenyl and Naphthyl Sulfonyl:Substituents R^(P)

In one embodiment, each R^(P) is independently selected from:

-   -   halo; hydroxy; ether (e.g., C₁₋₇alkoxy); formyl; acyl (e.g.,        C₁₋₇alkylacyl, C₅₋₂₀arylacyl); carboxy; ester; acyloxy; amido;        acylamido; thioamido; tetrazolyl; amino; nitro; azido; cyano;        cyanato; thiocyano; isothiocyano; sulfhydryl; thioether (e.g.,        C₁₋₇alkylthio); sulfonic acid; sulfonate; sulfonyl; sulfonyloxy;        sulfinyloxy; sulfamino; sulfonamino; sulfinamino; sulfamyl;        sulfonamido; C₁₋₇alkyl (including, e.g., unsubstituted        C₁₋₇alkyl, C₁₋₇haloalkyl, C₁₋₇hydroxyalkyl, C₁₋₇carboxyalkyl,        C₁₋₇aminoalkyl, C₅₋₂₀aryl-C₁₋₇alkyl); C₃₋₂₀heterocyclyl; and        C₅₋₂₀aryl (including, e.g., C₅₋₂₀carboaryl, C₅₋₂₀heteroaryl,        C₁₋₇alkyl-C₅₋₂₀aryl and C₅₋₂₀haloaryl).

In one embodiment, each R^(P) is independently selected from:

-   -   hydroxy (—OH);    -   halo;    -   cyano (—CN);    -   carboxy (—COOH);    -   azido;    -   ester;    -   amino, including e.g.,        -   C₁₋₇alkyl-amino;        -   amino-C₁₋₇alkyl-amino (e.g., —NH(CH₂)_(w)-amino);    -   C₁₋₇alkyl, including, e.g.,        -   halo-C₁₋₇alkyl;        -   amino-C₁₋₇alkyl (e.g., —(CH₂)_(w)-amino);        -   carboxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—COOH);        -   hydroxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—OH);        -   C₅₋₂₀aryl-C₁₋₇alkyl;    -   ether, including, e.g.,        -   C₁₋₇alkoxy;        -   halo-C₁₋₇alkoxy;        -   amino-C₁₋₇alkoxy (e.g., —O(CH₂)_(w)-amino);        -   carboxy-C₁₋₇alkoxy (e.g., —O(CH₂)_(w)—COOH);        -   hydroxy-C₁₋₇alkoxy (e.g., —O(CH₂)_(w)—OH);        -   C₅₋₂₀aryl-C₁₋₇alkoxy;    -   acyl, including, e.g.,        -   C₁₋₇alkyl-acyl;        -   halo-C₁₋₇alkyl-acyl;        -   amino-C₁₋₇alkyl-acyl (e.g., —C(═O)(CH₂)_(w)-amino);        -   carboxy-C₁₋₇alkyl-acyl (e.g., —C(═O)(CH₂)_(w)—COOH);        -   hydroxy-C₁₋₇alkyl-acyl (e.g., —C(═O)(CH₂)_(w)—OH);        -   C₅₋₂₀aryl-C₁₋₇alkyl-acyl;        -   C₅₋₂₀aryl-acyl;    -   C₅₋₂₀aryl;    -   wherein w is an integer from 1 to 7, preferably 1 to 4,        preferably 1, 2, or 3.

In one embodiment, each R^(P) is independently selected from:

-   -   —OH;    -   —F, —Cl, —Br, —I;    -   —CN;    -   —COOH;    -   —N₃;    -   —COOMe, —COOEt, —COOtBu, —COOPh, —COOCH₂Ph;    -   —NH₂, —NHMe, —NHEt, —NMe₂, —NEt₂;    -   piperidino, morpholino, piperazino, N-methyl-piperazino;    -   —NH(CH₂)_(w)—NH₂, —NH(CH₂)_(w)—NHMe, —NH(CH₂)_(w)—NMe₂,        —NH(CH₂)_(w)—NEt₂;    -   -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu;    -   —CH₂F, —CH₂Cl, —CF₃, —CCl₃, —CF₂CF₃, —CH₂CF₃, —C(CF₃)₃;    -   —(CH₂)_(w)—NH₂, —(CH₂)_(w)—NHMe, —(CH₂)_(w)—NMe₂,        —(CH₂)_(w)—NEt₂;    -   —(CH₂)_(w)—COOH;    -   —(CH₂)_(w)—OH;    -   —CH₂Ph;    -   —OMe, —OEt, -OnPr, -OiPr, -OnBu, -OiBu, —OsBu, -OtBu;    -   —OCH₂F, —OCH₂Cl, —OCF₃, —OCCl₃, —OCF₂CF₃, —OCH₂CF₃, —OC(CF₃)₃;    -   —O(CH₂)_(w)—NH₂, —O(CH₂)_(w)—NHMe, —O(CH₂)_(w)—NMe₂,        —O(CH₂)_(w)—NEt₂;    -   —O(CH₂)_(w)—COOH;    -   —O(CH₂)_(w)—OH;    -   —OCH₂Ph;    -   —C(═O)Me, —C(═O)Et, —C(═O)-nPr, —C(═O)-iPr, —C(═O)-nBu,        —C(═O)-iBu,    -   —C(═O)-sBu, —C(═O)-tBu;    -   —C(═O)CH₂F, —C(═O)CH₂Cl, —C(═O)CF₃, —C(═O)CCl₃, —C(═O)CF₂CF₃,    -   —C(═O)CH₂CF₃, —C(═O)C(CF₃)₃;    -   —C(═O)(CH₂)_(w)—NH₂, —C(═O)(CH₂)_(w)—NHMe, —C(═O)(CH₂)_(w)—NMe₂,    -   —C(═O)(CH₂)_(w)—NEt₂;    -   —C(═O)(CH₂)_(w)—COOH;    -   —C(═O)(CH₂)_(w)—OH;    -   —C(═O)CH₂Ph;    -   -Ph;    -   wherein w is an integer from 1 to 7, preferably 1 to 4,        preferably 1, 2, or 3.

In one embodiment, each R^(P) is independently selected from:

-   -   hydroxy (—OH);    -   halo;    -   C₁₋₇alkyl;    -   halo-C₁₋₇alkyl;    -   C₁₋₇alkoxy;    -   halo-C₁₋₇alkyl.

In one embodiment, each R^(P) is independently selected from:

-   -   —OH;    -   —F, —Cl, —Br, —I;    -   -Me, -Et;    -   —CF₃, —CH₂CF₃, —C₄F₉;    -   —OMe, —OEt;    -   —OCF₃, —OCH₂CF₃, —OC₄F₉.

In one embodiment, each R^(P) is independently selected from:

-   -   halo;    -   C₁₋₇alkyl;    -   C₁₋₇alkoxy.

In one embodiment, each R^(P) is independently selected from:

-   -   —F, —Cl, —Br, —I, -Me, -Et, —OMe, —OEt.

In one embodiment, each R^(P) is independently selected from:

-   -   —F, -Me, —OMe.

The Indol-2-yl Ring Substituents: R^(3N), R^(4N), R^(5N), R^(6N), andR^(7N)

In one embodiment, each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently —H, or as defined above for R^(P).

In one embodiment, each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently —H, or selected from:

-   -   hydroxy (—OH);    -   halo;    -   C₁₋₇alkyl;    -   C₁₋₇alkoxy.

In one embodiment, each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently selected from:

-   -   —H, —OH, —F, —Cl, —Br, —I, -Me, -Et, —OMe, —OEt.

In one embodiment, each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently —H, or selected from:

-   -   halo;    -   C₁₋₇alkyl;    -   C₁₋₇alkoxy.

In one embodiment, each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently selected from:

-   -   —H, —F, —Cl, —Br, —I, -Me, -Et, —OMe, —OEt.

In one embodiment, each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently selected from:

-   -   —H, —F, —OMe.

In one embodiment, R^(3N) is —H.

In one embodiment, each of R^(4N) and R^(7N) is —H.

In one embodiment, each of R^(3N), R^(4N) and R^(7N) is —H.

In one embodiment, each of R^(4N), R^(6N), and R^(7N) is —H.

In one embodiment, each of R^(3N), R^(4N), R^(6N), and R^(7N) is —H.

In one embodiment, each of R^(4N), R^(5N), and R^(7N) is —H.

In one embodiment, each of R^(3N), R^(4N), R^(5N), and R^(7N) is —H.

In one embodiment, each of R^(5N), R^(6N), and R^(7N) is —H.

In one embodiment, each of R^(3N), R^(5N), R^(6N), and R^(7N) is —H.

In one embodiment, each of R^(4N), R^(5N), and R^(6N) is —H.

In one embodiment, each of R^(3N), R^(4N), R^(5N), and R^(6N) is —H.

In one embodiment, each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) is—H.

Examples of Specific Embodiments

Some individual embodiments of the present invention include thefollowing compounds:

SIQ-01

SIQ-02

SIQ-03

SIQ-04

SIQ-05

SIQ-06

SIQ-07

SIQ-08

SIQ-09

SIQ-10

SIQ-11

Examples of additional individual embodiments of the present inventioninclude the following compounds:

SIQ-12

SIQ-13

SIQ-14

SIQ-15

SIQ-16

Chemical Terms

The term “carbo,” “carbyl,” “hydrocarbon” and “hydrocarbyl,” as usedherein, pertain to compounds and/or groups which have only carbon andhydrogen atoms (but see “carbocyclic” below).

The term “hetero,” as used herein, pertains to compounds and/or groupswhich have at least one heteroatom, for example, multivalent heteroatoms(which are also suitable as ring heteroatoms) such as boron, silicon,nitrogen, phosphorus, oxygen, sulfur, and selenium (more commonlynitrogen, oxygen, and sulfur) and monovalent heteroatoms, such asfluorine, chlorine, bromine, and iodine.

The term “saturated,” as used herein, pertains to compounds and/orgroupswhich do not have any carbon-carbon double bonds or carbon-carbon triplebonds.

The term “unsaturated,” as used herein, pertains to compounds and/orgroups which have at least one carbon-carbon double bond orcarbon-carbon triple bond. Compounds and/or groups may be partiallyunsaturated or fully unsaturated.

The term “aliphatic,” as used herein, pertains to compounds and/orgroups which are linear or branched, but not cyclic (also known as“acyclic” or “open-chain” groups).

The term “ring,” as used herein, pertains to a closed ring of from 3 to10 covalently linked atoms, more preferably 3 to 8 covalently linkedatoms, yet more preferably 5 to 6 covalently linked atoms. A ring may bean alicyclic ring or an aromatic ring. The term “alicyclic ring,” asused herein, pertains to a ring which is not an aromatic ring.

The term “carbocyclic ring,” as used herein, pertains to a ring whereinall of the ring atoms are carbon atoms.

The term “carboaromatic ring,” as used herein, pertains to an aromaticring wherein all of the ring atoms are carbon atoms.

The term “heterocyclic ring,” as used herein, pertains to a ring whereinat least one of the ring atoms is a multivalent ring heteroatom, forexample, nitrogen, phosphorus, silicon, oxygen, or sulfur, though morecommonly nitrogen, oxygen, or sulfur. Preferably, the heterocyclic ringhas from 1 to 4 heteroatoms.

The term “cyclic compound,” as used herein, pertains to a compound whichhas at least one ring. The term “cyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a cyclic compound.

Where a cyclic compound has two or more rings, they may be fused (e.g.,as in naphthalene, decalin, etc.), bridged (e.g., as in norbornane,adamantane, etc.), spiro (e.g., as in spiro[3.3]heptane), or acombination thereof. Cyclic compounds with one ring may be referred toas “monocyclic” or “mononuclear,” whereas cyclic compounds with two ormore rings may be referred to as “polycyclic” or “polynuclear.”

The term “carbocyclic compound,” as used herein, pertains to a cycliccompound which has only carbocyclic ring(s).

The term “heterocyclic compound,” as used herein, pertains to a cycliccompound which has at least one heterocyclic ring.

The term “aromatic compound,” as used herein, pertains to a cycliccompound which has at least one aromatic ring.

The term “carboaromatic compound,” as used herein, pertains to a cycliccompound which has only carboaromatic ring(s).

The term “heteroaromatic compound,” as used herein, pertains to a cycliccompound which has at least one heteroaromatic ring.

The term “monodentate substituents,” as used herein, pertains tosubstituents which have one point of covalent attachment.

The term “monovalent monodentate substituents,” as used herein, pertainsto substituents which have one point of covalent attachment, via asingle bond. Examples of such substituents include halo, hydroxy, andalkyl.

The term “multivalent monodentate substituents,” as used herein,pertains to substituents which have one point of covalent attachment,but through a double bond or triple bond. Examples of such substituentsinclude oxo, imino, alkylidene, and alklidyne.

The term “bidentate substituents,” as used herein, pertains tosubstituents which have two points of covalent attachment, and which actas a linking group between two other moieties. Examples of suchsubstituents include alkylene and arylene.

Substituents

The phrase “optionally substituted,” as used herein, pertains to aparent group which may be unsubstituted or which may be substituted.

Unless otherwise specified, the term “substituted,” as used herein,pertains to a parent group which bears one or more substitutents. Theterm “substituent” is used herein in the conventional sense and refersto a chemical moiety which is covalently attached to, or if appropriate,fused to, a parent group. A wide variety of substituents are well known,and methods for their formation and introduction into a variety ofparent groups are also well known.

Examples of substituents are described in more detail below.

Alkyl: The term “alkyl,” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from a carbon atom of a hydrocarboncompound having from 1 to 20 carbon atoms (unless otherwise specified),which may be aliphatic or alicyclic, and which may be saturated orunsaturated (e.g., partially unsaturated, fully unsaturated). Thus, theterm “alkyl” includes the sub-classes alkenyl, alkynyl, cycloalkyl,cycloalkyenyl, cycloalkynyl, etc., discussed below.

In the context of alkyl groups, the prefixes (e.g., C₁₋₄, C₁₋₇, C₁₋₂₀,C₂₋₇, C₃₋₇, etc.) denote the number of carbon atoms, or range of numberof carbon atoms. For example, the term “C₁₋₄alkyl,” as used herein,pertains to an alkyl group having from 1 to 4 carbon atoms. Examples ofgroups of alkyl groups include C₁₋₄alkyl (“lower alkyl”), C₁₋₇alkyl, andC₁₋₂₀alkyl. Note that the first prefix may vary according to otherlimitations; for example, for unsaturated alkyl groups, the first prefixmust be at least 2; for cyclic alkyl groups, the first prefix must be atleast 3; etc.

Examples of (unsubstituted) saturated alkyl groups include, but are notlimited to, methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl(C₅), hexyl (C₆), heptyl (C₇), octyl (C₈), nonyl (C₉), decyl (C₁₀),undecyl (C₁₁), dodecyl (C₁₂), tridecyl (C₁₃), tetradecyl (C₁₄),pentadecyl (C₁₅), and eicodecyl (C₂₀).

Examples of (unsubstituted) saturated linear alkyl groups include, butare not limited to, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl(C₄), n-pentyl (amyl) (C₅), n-hexyl (C₆), and n-heptyl (C₇).

Examples of (unsubstituted) saturated branched alkyl groups includeiso-propyl (C₃), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄),iso-pentyl (C₅), and neo-pentyl (C₅).

Alkenyl: The term “alkenyl,” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon double bonds. Examples of groups ofalkenyl groups include C₂₋₄alkenyl, C₂₋₇alkenyl, C₂₋₂₀alkenyl.

Examples of (unsubstituted) unsaturated alkenyl groups include, but arenot limited to, ethenyl (vinyl, —CH═CH₂), 1-propenyl (—CH═CH—CH₃),2-propenyl (allyl, —CH—CH═CH₂), isopropenyl (1-methylvinyl,—C(CH₃)═CH₂), butenyl (C₄), pentenyl (C₅), and hexenyl (C₆).

Alkynyl: The term “alkynyl,” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon triple bonds. Examples of groups ofalkynyl groups include C₂₋₄alkynyl, C₂₋₇alkynyl, C₂₋₂₀alkynyl.

Examples of (unsubstituted) unsaturated alkynyl groups include, but arenot limited to, ethynyl (ethinyl, —C≡CH) and 2-propynyl (propargyl,—CH₂C≡CH).

Cycloalkyl: The term “cycloalkyl,” as used herein, pertains to an alkylgroup which is also a cyclyl group; that is, a monovalent moietyobtained by removing a hydrogen atom from an alicyclic ring atom of acarbocyclic ring of a carbocyclic compound, which carbocyclic ring maybe saturated or unsaturated (e.g., partially unsaturated, fullyunsaturated), which moiety has from 3 to 20 carbon atoms (unlessotherwise specified), including from 3 to 20 ring atoms. Thus, the term“cycloalkyl” includes the sub-classes cycloalkyenyl and cycloalkynyl.Preferably, each ring has from 3 to 7 ring atoms. Examples of groups ofcycloalkyl groups include C₃₋₂₀cycloalkyl, C₃₋₁₅cycloalkyl,C₃₋₁₀cycloalkyl, C₃₋₇cycloalkyl.

Examples of cycloalkyl groups include, but are not limited to, thosederived from:

-   -   saturated monocyclic hydrocarbon compounds: cyclopropane (C₃),        cyclobutane (C₄), cyclopentane (C₅), cyclohexane (C₆),        cycloheptane (C₇), methylcyclopropane (C₄), dimethylcyclopropane        (C₅), methylcyclobutane (C₅), dimethylcyclobutane (C₆),        methylcyclopentane (C₆), dimethylcyclopentane (C₇),        methylcyclohexane (C₇), dimethylcyclohexane (C₈), menthane        (C₁₀);    -   unsaturated monocyclic hydrocarbon compounds: cyclopropene (C₃),        cyclobutene (C₄), cyclopentene (C₅), cyclohexene (C₆),        methylcyclopropene (C₄), dimethylcyclopropene (C₅),        methylcyclobutene (C₅), dimethylcyclobutene (C₆),        methylcyclopentene (C₆), dimethylcyclopentene (C₇),        methylcyclohexene (C₇), dimethylcyclohexene (C₈);    -   saturated polycyclic hydrocarbon compounds: thujane (C₁₀),        carane (C₁₀), pinane (C₁₀), bornane (C₁₀), norcarane (C₇),        norpinane (C₇), norbornane (C₇), adamantane (C₁₀), decalin        (decahydronaphthalene) (C₁₀);    -   unsaturated polycyclic hydrocarbon compounds: camphene (C₁₀),        limonene (C₁₀), pinene (C₁₀);    -   polycyclic hydrocarbon compounds having an aromatic ring: indene        (C₉), indane (e.g., 2,3-dihydro-1H-indene) (C₉), tetraline        (1,2,3,4-tetrahydronaphthalene) (C₁₀), acenaphthene (C₁₂),        fluorene (C₁₃), phenalene (C₁₃), acephenanthrene (C₁₅),        aceanthrene (C₁₆), cholanthrene (C₂₀).

Alkylidene: The term “alkylidene,” as used herein, pertains to adivalent monodentate moiety obtained by removing two hydrogen atoms froman aliphatic or alicyclic carbon atom of a hydrocarbon compound havingfrom 1 to 20 carbon atoms (unless otherwise specified). Examples ofgroups of alkylidene groups include C₁₋₂₀alkylidene, C₁₋₇alkylidene,C₁₋₄alkylidene.

Examples of alkylidene groups include, but are not limited to,methylidene (═CH₂), ethylidene (═CH—CH₃), vinylidene (═C═CH₂),isopropylidene (═C(CH₃)₂), cyclopentylidene. An example of a substitutedalkylidene group is benzylidene (═CH-Ph).

Alkylidyne: The term “alkylidyne,” as used herein, pertains to atrivalent monodentate moiety obtained by removing three hydrogen atomsfrom an aliphatic or alicyclic carbon atom of a hydrocarbon compoundhaving from 1 to 20 carbon atoms (unless otherwise specified). Examplesof groups of alkylidyne groups include C₁₋₂₀alkylidyne, C₁₋₇alkylidyne,C₁₋₄alkylidyne.

Examples of alkylidyne groups include, but are not limited to,methylidyne (≡CH) and ethylidyne (≡C—CH₃). An example of a substitutedalkylidene group is benzylidyne (≡C-Ph).

Carbocyclyl: The term “carbocyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a carbocyclic compound, which moiety has from 3 to 20 ring atoms(unless otherwise specified). Preferably, each ring has from 3 to 7 ringatoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms. For example, theterm “C₅₋₆carbocyclyl,” as used herein, pertains to a carbocyclyl grouphaving 5 or 6 ring atoms. Examples of groups of carbocyclyl groupsinclude C₃₋₂₀carbocyclyl, C₃₋₁₀carbocyclyl, C₅₋₁₀ocarbocyclyl,C₃₋₇carbocyclyl, and C₅₋₇carbocyclyl.

Examples of carbocyclic groups include, but are not limited to, thosedescribed above as cycloalkyl groups; and those described below ascarboaryl groups.

Heterocyclyl: The term “heterocyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a heterocyclic compound, which moiety has from 3 to 20 ring atoms(unless otherwise specified), of which from 1 to 10 are ringheteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of whichfrom 1 to 4 are ring heteroatoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆heterocyclyl,” as usedherein, pertains to a heterocyclyl group having 5 or 6 ring atoms.Examples of groups of heterocyclyl groups include C₃₋₂₀heterocyclyl,C₅₋₂₀heterocyclyl, C₃₋₁₅heterocyclyl, C₅₋₁₅heterocyclyl,C₃₋₁₂heterocyclyl, C₅₋₁₂heterocyclyl, C₃₋₁₀heterocyclyl,C₅₋₁₀heterocyclyl, C₃₋₇heterocyclyl, C₅₋₇heterocyclyl, andC₅₋₆heterocyclyl.

Examples of (non-aromatic) monocyclic heterocyclyl groups include, butare not limited to, those derived from:

N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole)(C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrroleor 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine (C₆),dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);

O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅), oxole(dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran (C₆),pyran (C₆), oxepin (C₇);

S₁: thiirane (C₃), thietahe (C₄), thiolane (tetrahydrothiophene) (C₅),thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);

O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);

O₃: trioxane (C₆);

N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline(C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);

N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅), tetrahydroisoxazole(C₅), dihydroisoxazole (C₅), morpholine (C₆), tetrahydrooxazine (C₆),dihydrooxazine (C₆), oxazine (C₆);

N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);

N₂O₁: oxadiazine (C₆);

O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,

N₁O₁S₁: oxathiazine (C₆).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groupsinclude those derived from saccharides, in cyclic form, for example,furanoses (C₅), such as arabinofuranose, lyxofuranose, ribofuranose, andxylofuranse, and pyranoses (C₆), such as allopyranose, altropyranose,glucopyranose, mannopyranose, gulopyranose, idopyranose,galactopyranose, and talopyranose.

Examples of heterocyclyl groups which are also heteroaryl groups aredescribed below with aryl groups.

Aryl: The term “aryl,” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from an aromatic ring atom of anaromatic compound, which moiety has from 3 to 20 ring atoms (unlessotherwise specified). Preferably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆aryl,” as used herein,pertains to ani aryl group having 5 or 6 ring atoms. Examples of groupsof aryl groups include C₃₋₂₀aryl, C₅₋₂₀aryl, C₅₋₁₅aryl, C₅₋₁₂aryl,C₅₋₁₀aryl, C₅₋₇aryl, C₅₋₆aryl, C₅aryl, and C₆aryl.

The ring atoms may be all carbon atoms, as in “carboaryl groups.”Examples of carboaryl groups include C₃₋₂₀carboaryl, C₅₋₂₀carboaryl,C₅₋₁₅carboaryl, C₅₋₁₂carboaryl, C₅₋₁₀carboaryl, C₅₋₇carboaryl,C₅₋₆carboaryl, C₅carboaryl, and C₆carboaryl.

Examples of carboaryl groups include, but are not limited to, thosederived from benzene (i.e., phenyl) (C₆), naphthalene (C₁₀), azulene(C₁₀), anthracene (C₁₄), phenanthrene (C₁₄), naphthacene (C₁₈), andpyrene (C₁₆).

Examples of aryl groups which comprise fused rings, at least one ofwhich is an aromatic ring, include, but are not limited to, groupsderived from indane (e.g., 2,3-dihydro-1H-indene) (C₉), indene (C₉),isoindene (C₉), tetraline (1,2,3,4-tetrahydronaphthalene (C₁₀),acenaphthene (C₁₂), fluorene (C₁₃), phenalene (C₁₃), acephenanthrene(C₁₅), and aceanthrene (C₁₆).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroaryl groups.” Examples of heteroaryl groups includeC₃₋₂₀heteroaryl, C₅₋₂₀heteroaryl, C₅₋₁₅heteroaryl, C₅₋₁₂heteroaryl,C₅₋₁₀heteroaryl, C₅₋₇heteroaryl, C₅₋₆heteroaryl, C₅heteroaryl, andC₆heteroaryl.

Examples of monocyclic heteroaryl groups include, but are not limitedto, those derived from:

N₁: pyrrole (azole) (C₅), pyridine (azine) (C₆);

O₁: furan (oxole) (C₅);

S₁: thiophene (thiole) (C₅);

N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆);

N₂O₁: oxadiazole (furazan) (C₅);

N₃O₁: oxatriazole (C₅);

N₁S₁: thiazole (C₅), isothiazole (C₅);

N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅),pyridazine (1,2-diazine) (C₆), pyrimidine (1,3-diazine) (C₆) (e.g.,cytosine, thymine, uracil), pyrazine (1,4-diazine) (C₆);

N₃: triazole (C₅), triazine (C₆); and,

N₄: tetrazole (C₅).

Examples of heterocyclic groups (some of which are also heteroarylgroups) which comprise fused rings, include, but are not limited to:

-   -   C₉heterocyclic groups (with 2 fused rings) derived from        benzofuran (O₁), isobenzofuran (O₁), indole (N₁), isoindole        (N₁), indolizine (N₁), indoline (N₁), isoindoline (N₁), purine        (N₄) (e.g., adenine, guanine), benzimidazole (N₂), indazole        (N₂), benzoxazole (N₁O₁), benzisoxazole (N₁O₁), benzodioxole        (O₂), benzofurazan (N₂O₁), benzotriazole (N₃), benzothiofuran        (S₁), benzothiazole (N₁S₁), benzothiadiazole (N₂S);    -   C₁₀heterocyclic groups (with 2 fused rings) derived from        chromene (O₁), isochromene (O₁), chroman (O₁), isochroman (O₁),        benzodioxan (O₂), quinoline (N₁), isoquinoline (N₁), quinolizine        (N₁), benzoxazine (N₁O₁), benzodiazine (N₂), pyridopyridine        (N₂), quinoxaline (N₂), quinazoline (N₂), cinnoline (N₂),        phthalazine (N₂), naphthyridine (N₂), pteridine (N₄);    -   C₁₁heterocylic groups (with 2 fused rings) derived from        benzodiazepine (N₂);    -   C₁₃heterocyclic groups (with 3 fused rings) derived from        carbazole (N₁), dibenzofuran (O₁), dibenzothiophene (S₁),        carboline (N₂), perimidine (N₂), pyridoindole (N₂); and,    -   C₁₄heterocyclic groups (with 3 fused rings) derived from        acridine (N₁), xanthene (O₁), thioxanthene (S₁), oxanthrene        (O₂), phenoxathiin (O₁S₁), phenazine (N₂), phenoxazine (N₁O₁),        phenbthiazine (N₁S₁), thianthrene (S₂), phenanthridine (N₁),        phenanthroline (N₂), phenazine (N₂).

Heterocyclic groups (including heteroaryl groups) which have a nitrogenring atom in the form of an —NH— group may be N-substituted, that is, as—NR—. For example, pyrrole may be N-methyl substituted, to giveN-methylpyrrole. Examples of N-substitutents include, but are notlimited to C₁₋₇alkyl, C₃₋₂₀heterocyclyl, C₅₋₂₀aryl, and acyl groups.

Heterocyclic groups (including heteroaryl groups) which have a nitrogenring atom in the form of an —N═ group may be substituted in the form ofan N-oxide, that is, as —N(→O)═ (also denoted —N⁺(→O⁻)═). For example,quinoline may be substituted to give quinoline N-oxide; pyridine to givepyridine N-oxide; benzofurazan to give benzofurazan N-oxide (also knownas benzofuroxan).

Cyclic groups may additionally bear one or more oxo (═O) groups on ringcarbon atoms.

Monocyclic examples of such groups include, but are not limited to,those derived from:

C₅: cyclopentanone, cyclopentenone, cyclopentadienone;

C₆: cyclohexanone, cyclohexenone, cyclohexadienone;

O₁: furanone (C₅), pyrone (C₆);

N₁: pyrrolidone (pyrrolidinone) (C₅), piperidinone (piperidone) (C₆),piperidinedione (C₆);

N₂: imidazolidone (imidazolidinone) (C₅), pyrazolone (pyrazolinone)(C₅), piperazinone (C₆), piperazinedione (C₆), pyridazinone (C₆),pyrimidinone (C₆) (e.g., cytosine), pyrimidinedione (C₆) (e.g., thymine,uracil), barbituric acid (C₆);

N₁S₁: thiazolone (C₅), isothiazolone (C₅);

N₁O₁: oxazolinone (C₅).

Polycyclic examples of such groups include, but are not limited to,those derived from:

C₉: indenedione;

C₁₀: tetralone, decalone;

C₁₄: anthrone, phenanthrone;

N₁: oxindole (C₉);

O₁: benzopyrone (e.g., coumarin, isocoumarin, chromone) (C₁₀);

N₁O₁: benzoxazolinone (C₉), benzoxazolinone (C₁₀);

N₂: quinazolinedione (C₁₀); benzodiazepinone (C₁₁); benzodiazepinedione(C₁₁);

N₄: purinone (C₉) (e.g., guanine).

Still more examples of cyclic groups which bear one or more oxo (═O)groups on ring carbon atoms include, but are not limited to, thosederived from:

-   -   cyclic anhydrides (—C(═O)—O—C(═O)— in a ring), including but not        limited to maleic anhydride (C₅), succinic anhydride (C₅), and        glutaric anhydride (C₆);    -   cyclic carbonates (—O—C(═O)—O— in a ring), such as ethylene        carbonate (C₅) and 1,2-propylene carbonate (C₅);    -   imides (—C(═O)—NR—C(═O)— in a ring), including but not limited        to, succinimide (C₅), maleimide (C₅), phthalimide, and        glutarimide (C₆);    -   lactones (cyclic esters, —O—C(═O)— in a ring), including, but        not limited to, β-propiolactone, γ-butyrolactone,        δ-valerolactone (2-piperidone), and ε-caprolactone;    -   lactams (cyclic amides, —NR—C(═O)— in a ring), including, but        not limited to, β-propiolactam (C₄), γ-butyrolactam        (2-pyrrolidone) (C₅), δ-valerolactam (C₆), and ε-caprolactam        (C₇);    -   cyclic carbamates (—O—C(═O)—NR— in a ring), such as        2-oxazolidone (C₅); cyclic ureas (—NR—C(═O)—NR— in a ring), such        as 2-imidazolidone (C₅) and pyrimidine-2,4dione (e.g., thymine,        uracil) (C₆).

The above alkyl, alkylidene, alkylidyne, heterocyclyl, and aryl groups,whether alone or part of another substituent, may themselves optionallybe substituted with one or more groups selected from themselves and theadditional substituents listed below.

Hydrogen: —H. Note that if the substituent at a particular position ishydrogen, it may be convenient to refer to the compound as being“unsubstituted” at that position.

Halo: —F, —Cl, —Br, and —I.

Hydroxy: —OH.

Ether: —OR, wherein R is an ether substituent, for example, a C₁₋₇alkylgroup (also referred to as a C₁₋₇alkoxy group, discussed below), aC₃₋₂₀heterocyclyl group (also referred to as a C₃₋₂₀heterocyclyloxygroup), or a C₅₋₂₀aryl group (also referred to as a C₅₋₂₀aryloxy group),preferably a C₁₋₇alkyl group.

C₁₋₇alkoxy: —OR, wherein R is a C₁₋₇alkyl group. Examples of C₁₋₇alkoxygroups include, but are not limited to, —OMe (methoxy), —OEt (ethoxy),—O(nPr) (n-propoxy), —O(iPr) (isopropoxy), —O(nBu) (n-butoxy), —O(sBu)(sec-butoxy), —O(iBu) (isobutoxy), and —O(tBu) (tert-butoxy).

Acetal: —CH(OR¹)(OR²), wherein R¹ and R² are independently acetalsubstituents, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group, or, in the case of a“cyclic” acetal group, R¹and R², taken together with the two oxygenatoms to which they are attached, and the carbon atoms to which they areattached, form a heterocyclic ring having from 4 to 8 ring atoms.Examples of acetal groups include, but are not limited to, —CH(OMe)₂,—CH(OEt)₂, and —CH(OMe)(OEt).

Hemiacetal: —CH(OH)(OR¹), wherein R¹ is a hemiacetal substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of hemiacetal groupsinclude, but are not limited to, —CH(OH)(OMe) and —CH(OH)(OEt).

Ketal: —CR(OR¹)(OR²), where R¹ and R² are as defined for acetals, and Ris a ketal substituent other than hydrogen, for example, a C₁₋₇alkylgroup, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably aC₁₋₇alkyl group. Examples ketal groups include, but are not limited to,—C(Me)(OMe)₂, —C(Me)(OEt)₂, —C(Me)(OMe)(OEt), —C(Et)(OMe)₂,—C(Et)(OEt)₂, and —C(Et)(OMe)(OEt).

Hemiketal: —CR(OH)(OR¹), where R¹ is as defined for hemiacetals, and Ris a hemiketal substituent other than hydrogen, for example, a C₁₋₇alkylgroup, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably aC₁₋₇alkyl group. Examples of hemiacetal groups include, but are notlimited to, —C(Me)(OH)(OMe), —C(Et)(OH)(OMe), —C(Me)(OH)(OEt), and—C(Et)(OH)(OEt).

Oxo (keto, -one): ═O.

Thione (thioketone): ═S.

Imino (imine): ═NR, wherein R is an imino substituent, for example,hydrogen, C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably hydrogen or a C₁₋₇alkyl group. Examples of estergroups include, but are not limited to, ═NH, ═NMe, NEt, and ═NPh.

Formyl (carbaldehyde, carboxaldehyde): —C(═O)H.

Acyl (keto): —C(═O)R, wherein R is an acyl substituent, for example, aC₁₋₇alkyl group (also referred to as C₁₋₇alkylacyl or C₁₋₇alkanoyl), aC₃₋₂₀heterocyclyl group (also referred to as C₃₋₂₀heterocyclylacyl), ora C₅₋₂₀aryl group (also referred to as C₅₋₂₀arylacyl), preferably aC₁₋₇alkyl group. Examples of acyl groups include, but are not limitedto, —C(═O)CH₃ (acetyl), —C(═O)CH₂CH₃ (propionyl), —C(═O)C(CH₃)₃(t-butyryl), and —C(═O)Ph (benzoyl, phenone).

Carboxy (carboxylic acid): —C(═O)OH.

Thiocarboxy (thiocarboxylic acid): —C(═S)SH.

Thiolocarboxy (thiolocarboxylic acid): —C(═O)SH.

Thionocarboxy (thionocarboxylic acid): —C(═S)OH.

Imidic acid: —C(═NH)OH.

Hydroxamic acid: —C(═NOH)OH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR,wherein R is an ester substituent, for example, a C₁₋₇alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkylgroup. Examples of ester groups include, but are not limited to,—C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

Acyloxy (reverse ester): —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of acyloxygroups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): —C(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of amido groups include, but are not limited to,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², togetherwith the nitrogen atom to which they are attached, form a heterocyclicstructure as in, for example, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, and piperazinocarbonyl.

Acylamido (acylamino): —NR¹C(═O)R², wherein R¹ is an amide substituent,for example, hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, ora C₅₋₂₀aryl group, preferably hydrogen or a C₁₋₇alkyl group, and R² isan acyl substituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclylgroup, or a C₅₋₂₀aryl group, preferably hydrogen or a C₁₋₇alkyl group.Examples of acylamide groups include, but are not limited to,—NHC(═O)CH₃, —NHC(═O)CH₂CH₃, and —NHC(═O)Ph. R¹ and R² may together forma cyclic structure, as in, for example, succinimidyl, maleimidyl, andphthalimidyl:

Thioamido (thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² areindependently amino substituents, as defined for amino groups. Examplesof amido groups include, but are not limited to, —C(═S)NH₂, —C(═S)NHCH₃,—C(═S)N(CH₃)₂, and —C(═S)NHCH₂CH₃.

Ureido: —N(R¹)CONR²R³ wherein R² and R³ are independently aminosubstituents, as defined for amino groups, and R1is a ureidosubstituent, for example, hydrogen, a C₁₋₇alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably hydrogen or aC₁₋₇alkyl group. Examples of ureido groups include, but are not limitedto, —NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂, —NMeCONH₂,—NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, and —NMeCONEt₂.

Guanidino: —NH—C(═NH)NH₂.

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms andone carbon atom,

Amino: —NR¹R², wherein R¹ and R² are independently amino substituents,for example, hydrogen, a C₁₋₇alkyl group (also referred to asC₁₋₇alkylamino or di-C₁₋₇alkylamino), a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group, or, in the case of a“cyclic” amino group, R¹ and R², taken together with the nitrogen atomto which they are attached, form a heterocyclic ring having from 4 to 8ring atoms. Amino groups may be primary (—NH₂), secondary (—NHR¹), ortertiary (—NHR¹R²), and in cationic form, may be quaternary (—⁺NR¹R²R³).Examples of amino groups include, but are not limited to, —NH₂, —NHCH₃,—NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples of cyclic aminogroups include, but are not limited to, aziridino, azetidino,pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.

Imino: ═NR, wherein R is an imino substituent, for example, for example,hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably H or a C₁₋₇alkyl group. Examples of imino groupsinclude, but are not limited to, ═NH, ═NMe, and ═NEt.

Amidine (amidino): —C(═NR)NR₂, wherein each R is an amidine substituent,for example, hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, ora C₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group. Examples ofamidine groups include, but are not limited to, —C(═NH)NH₂, —C(═NH)NMe₂,and —C(═NMe)NMe₂.

Nitro: —NO₂.

Azido: —N₃.

Cyano (nitrile, carbonitrile): —CN.

Cyanato: —OCN.

Thiocyano (thiocyanato): —SCN.

Isothiocyano (isothiocyanato): —NCS.

Sulfhydryl (thiol, mercapto): —SH.

Thioether (sulfide): —SR, wherein R is a thioether substituent, forexample, a C₁₋₇alkyl group (also referred to as a C₁₋₇alkylthio group),a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkylgroup. Examples of C₁₋₇alkylthio groups include, but are not limited to,—SCH₃ and —SCH₂CH₃.

Disulfide: —SS—R, wherein R is a disulfide substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group (also referred to herein as C₁₋₇alkyldisulfide). Examples of C₁₋₇alkyl disulfide groups include, but are notlimited to, —SSCH₃ and —SSCH₂CH₃.

Sulfonic acid (sulfo): —S(═O)₂OH, —SO₃H.

Sulfonate (sulfonic acid ester): —S(═O)₂OR, wherein R is a sulfonatesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples ofsulfonate groups include, but are not limited to, —S(═O)₂OCH₃ and—S(═O)₂OCH₂CH₃.

Sulfinic acid: —S(═O)OH, —SO₂H.

Sulfinate (sulfinic acid ester): —S(═O)OR; wherein R is a sulfinatesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples ofsulfinate groups include, but are not limited to, —S(═O)OCH₃ and—S(═O)OCH₂CH₃.

Sulfate: —OS(═O)₂OR; wherein R is a sulfate substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfate groups include, butare not limited to, —OS(═O)₂OCH₃ and —SO(═O)₂OCH₂CH₃.

Sulfone (sulfonyl): —S(═O)₂R, wherein R is a sulfone substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group, for example, a fluorinated orperfluorinated C₁₋₇alkyl group. Examples of sulfone groups include, butare not limited to, —S(═O)₂CH₃ (methanesulfonyl, mesyl), —S(═O)₂CF₃(triflyl), —S(═O)₂CH₂CH₃ (esyl), —S(═O)₂C₄F₉ (nonaflyl), —S(═O)₂CH₂CF₃(tresyl), —S(═O)₂Ph (phenylsulfonyl, besyl), 4-methylphenylsulfonyl(tosyl), 4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl(brosyl), 4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and5-dimethylamino-naphthalen-1-ylsulfonate (dansyl).

Sulfine (sulfinyl, sulfoxide): —S(═O)R, wherein R is a sulfinesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of sulfinegroups include, but are not limited to, —S(═O)CH₃ and —S(═O)CH₂CH₃.

Sulfonyloxy: —OS(═O)₂R, wherein R is a sulfonyloxy substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfonyloxy groupsinclude, but are not limited to, —OS(═O)₂CH₃ (mesylate) and—OS(═O)₂CH₂CH₃ (esylate).

Sulfinyloxy: —OS(═O)R, wherein R is a sulfinyloxy substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfinyloxy groupsinclude, but are not limited to, —OS(═O)CH₃ and —OS(═O)CH₂CH₃.

Sulfamino: —NR¹S(═O)₂OH, wherein R¹ is an amino substituent, as definedfor amino groups. Examples of sulfamino groups include, but are notlimited to, —NHS(═O)₂OH and —N(CH₃)S(═O)₂OH.

Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfonamino substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfonamino groups include,but are not limited to, —NHS(═O)₂CH₃ and —N(CH₃)S(═O)₂C₆H₅.

Sulfinamino: —NR¹S(═O)R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfinamino substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfinamino groups include,but are not limited to, —NHS(═O)CH₃ and —N(CH₃)S(═O)C₆H₅.

Sulfamyl: —S(═O)NR¹R², wherein R¹ and R² are independently aminosubstituents, as defined for amino groups. Examples of sulfamyl groupsinclude, but are not limited to, —S(═O)NH₂, —S(═O)NH(CH₃),—S(═O)N(CH₃)₂, —S(═O)NH(CH₂CH₃), —S(═O)N(CH₂CH₃)₂, and —S(═O)NH Ph.

Sulfonamido: —S(═O)₂NR¹R², wherein R¹ and R² are independently aminosubstituents, as defined for amino groups. Examples of sulfonamidogroups include, but are not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃),—S(═O)₂N(CH₃)₂, —S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂, and —S(═O)₂NHPh.

In many cases, substituents are themselves substituted.

For example, a C₁₋₇alkyl group may be substituted with, for example:

hydroxy (also referred to as a hydroxy-C₁₋₇alkyl group);

halo (also referred to as a halo-C₁₋₇alkyl group);

amino (also referred to as a amino-C₁₋₇alkyl group);

carboxy (also referred to as a carboxy-C₁₋₇alkyl group);

C₁₋₇alkoxy (also referred to as a C₁₋₇alkoxy-C₁₋₇alkyl group);

C₅₋₂₀aryl (also referred to as a C₅₋₂₀aryl-C₁₋₇alkyl group).

Similarly, a C₅₋₂₀aryl group may be substituted with, for example:

hydroxy (also referred to as a hydroxy-C₅₋₂₀aryl group);

halo (also referred to as a halo-C₅₋₂₀aryl group);

amino (also referred to as an amino-C₅₋₂₀aryl group, e.g., as inaniline);

carboxy (also referred to as an carboxy-C₅₋₂₀aryl group, e.g., as inbenzoic acid);

C₁₋₇alkyl (also referred to as a C₁₋₇alkyl-C₅₋₂₀aryl group, e.g., as intoluene);

C₁₋₇alkoxy (also referred to as a C₁₋₇alkoxy-C₅₋₂₀aryl group, e.g., asin anisole);

C₅₋₂₀aryl (also referred to as a C₅₋₂₀aryl-C₅₋₂₀aryl, e.g., as inbiphenyl).

These and other specific examples of such substituted-substituents aredescribed below.

Hydroxy-C₁₋₇alkyl: The term “hydroxy-C₁₋₇alkyl,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been replaced with a hydroxy group. Examples of such groupsinclude, but are not limited to, —CH₂OH, —CH₂CH₂OH, and —CH(OH)CH₂OH.

Halo-C₁₋₇alkyl group: The term “halo-C₁₋₇alkyl,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been replaced with a halogen atom (e.g., F, Cl, Br, I). Ifmore than one hydrogen atom has been replaced with a halogen atom, thehalogen atoms may independently be the same or different. Every hydrogenatom may be replaced with a halogen atom, in which case the group mayconveniently be referred to as a C₁₋₇per haloalkyl group.” Examples ofsuch groups include, but are not limited to, —CF₃, —CHF₂, —CH₂F, —CCl₃,—CBr₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃.

Amino-C₁₋₇alkyl: The term “amino-C₁₋₇alkyl,” as used herein, pertains toa C₁₋₇alkyl group in which at least one hydrogen atom (e.g., 1, 2, 3)has been replaced with an amino group. Examples of such groups include,but are not limited to, —CH₂NH₂, —CH₂CH₂NH₂, and —CH₂CH₂N(CH₃)₂.

Carboxy-C₁₋₇alkyl: The term “carboxy-C₁₋₇alkyl,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been replaced with a carboxy group. Examples of such groupsinclude, but are not limited to, —CH₂COOH and —CH₂CH₂COOH.

C₁₋₇alkoxy-C₁₋₇alkyl: The term “C₁₋₇alkoxy-C₁₋₇alkyl,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been replaced with a C₁₋₇alkoxy group. Examples of suchgroups include, but are not limited to, —CH₂OCH₃, —CH₂CH₂OCH₃, and,—CH₂CH₂OCH₂CH₃

C₅₋₂₀aryl-C₁₋₇alkyl: The term “C₅₋₂₀aryl-C₁₋₇alkyl,” as used herein,pertains to a C₁₋₇alkyl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been replaced with a C₅₋₂₀aryl group. Examples of suchgroups include, but are not limited to, benzyl (phenylmethyl, PhCH₂—),benzhydryl (Ph₂CH—), trityl (triphenylmethyl, Ph₃C—), phenethyl(phenylethyl, Ph-CH₂CH₂—), styryl (Ph-CH═CH—), cinnamyl (Ph-CH═CH—CH₂—).

Hydroxy-C₅₋₂₀aryl: The term “hydroxy-C₅₋₂₀aryl,” as used herein,pertains to a C₅₋₂₀aryl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been substituted with an hydroxy group. Examples of suchgroups include, but are not limited to, those derived from: phenol,naphthol, pyrocatechol, resorcinol, hydroquinone, pyrogallol,phloroglucinol.

Halo-C₅₋₂₀aryl: The term “halo-C₅₋₂₀aryl,” as used herein, pertains to aC₅₋₂₀aryl group in which at least one hydrogen atom (e.g., 1, 2, 3) hasbeen substituted with a halo (e.g., F, Cl, Br, I) group. Examples ofsuch groups include, but are not limited to, halophenyl (e.g.,fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl, whether ortho-,meta-, or para-substituted), dihalophenyl, trihalophenyl,tetrahalophenyl, and pentahalophenyl.

C₁₋₇alkyl-C₅₋₂₀aryl: The term “C₁₋₇alkyl-C₅₋₂₀aryl,” as used herein,pertains to a C₅₋₂₀aryl group in which at least one hydrogen atom (e.g.,1, 2, 3) has been substituted with a C₁₋₇alkyl group. Examples of suchgroups include, but are not limited to, tolyl (from toluene), xylyl(from xylene), mesityl (from mesitylene), and cumenyl (or cumyl, fromcumene), and duryl (from durene).

Hydroxy-C₁₋₇alkoxy: —OR, wherein R is a hydroxy-C₁₋₇alkyl group.Examples of hydroxy-C₁₋₇alkoxy groups include, but are not limited to,—OCH₂OH, —OCH₂CH₂OH, and —OCH₂CH₂CH₂OH.

Halo-C₁₋₇alkoxy: —OR, wherein R is a halo-C₁₋₇alkyl group. Examples ofhalo-C₁₋₇alkoxy groups include, but are not limited to, —OCF₃, —OCHF₂,—OCH₂F, —OCCl₃, —OCBr₃, —OCH₂CH₂F, —OCH₂CHF₂, and —OCH₂CF₃.

Carboxy-C₁₋₇alkoxy: —OR, wherein R is a carboxy-C₁₋₇alkyl group.Examples of carboxy-C₁₋₇alkoxy groups include, but are not limited to,—OCH₂COOH, —OCH₂CH₂COOH, and —OCH₂CH₂CH₂COOH.

C₁₋₇alkoxy-C₁₋₇alkoxy: —OR, wherein R is a C₁₋₇alkoxy-C₁₋₇alkyl group.Examples of C₁₋₇alkoxy-C₁₋₇alkoxy groups include, but are not limitedto, —OCH₂OCH₃, —OCH₂CH₂OCH₃, and —OCH₂CH₂OCH₂CH₃.

C₅₋₂₀aryl-C₁₋₇alkoxy: —OR, wherein R is a C₅₋₂₀aryl-C₁₋₇alkyl group.Examples of such groups include, but are not limited to, benzyloxy,benzhydryloxy, trityloxy, phenethoxy, styryloxy, and cimmamyloxy.

C₁₋₇alkyl-C₅₋₂₀aryloxy: —OR, wherein R is a C₁₋₇alkyl-C₅₋₂₀aryl group.Examples of such groups include, but are not limited to, tolyloxy,xylyloxy, mesityloxy, cumenyloxy, and duryloxy.

Amino-C₁₋₇alkyl-amino: The term “amino-C₁₋₇alkyl-amino,” as used herein,pertains to an amino group, —NR¹R², in which one of the substituents, R¹or R², is itself a amino-C₁₋₇alkyl group (—C₁₋₇alkyl-NR³R⁴). Theamino-C₁₋₇alkylamino group may be represented, for example, by theformula —NR¹—C₁₋₇alkyl-NR³R⁴. Examples of such groups include, but arenot limited to, groups of the formula —NR¹(CH₂)_(n)NR¹R², where n is 1to 6 (for example, —NHCH₂NH₂, —NH(CH₂)₂NH₂, —NH(CH₂)₃NH₂, —NH(CH₂)₄NH₂,—NH(CH₂)₅NH₂, —NH(CH₂)₆NH₂), —NHCH₂NH(Me), —NH(CH₂)₂NH(Me),—NH(CH₂)₃NH(Me), —NH(CH₂)₄NH(Me), —NH(CH₂)₅NH(Me), —NH(CH₂)₆NH(Me),—NHCH₂NH(Et), —NH(CH₂)₂NH(Et), —NH(CH₂)₃NH(Et), —NH(CH₂)₄NH(Et),—NH(CH₂)₅NH(Et), and —NH(CH₂)₆NH(Et).

Includes Other Forms

Unless otherwise specified, included in the above are the well knownionic, salt, solvate, and protected forms of these substituents. Forexample, a reference to carboxylic acid (—COOH) also includes theanionic (carboxylate) form (—COO⁻), a salt or solvate thereof, as wellas conventional protected forms. Similarly, a reference to an aminogroup includes the protonated form (—N⁺HR¹R²), a salt or solvate of theamino group, for example, a hydrochloride salt, as well as conventionalprotected forms of an amino group. Similarly, a reference to a hydroxylgroup also includes the anionic form (—O⁻), a salt or solvate thereof,as well as conventional protected forms of a hydroxyl group.

Isomers, Salts, Solvates, Protected Forms, and Prodrugs

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric,tautomeric, conformational, or anomeric forms, including but not limitedto, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo-and exo-forms; R—, S—, and meso-forms; D- and L-forms; d- and I-forms;(+) and (−) forms; keto-, enol-, and enolate-forms; syn- and anti-forms;synclinal- and anticlinal-forms; α- and β-forms; axial and equatorialforms; boat-, chair-, twist-, envelope-, and halfchair-forms; andcombinations thereof, hereinafter collectively referred to as “isomers”(or “isomeric forms”).

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁₋₇alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; F may be in any isotopic form, including¹⁸F and ¹⁹F; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including (wholly or partially)racemic and other mixtures thereof. Methods for the preparation (e.g.,asymmetric synthesis) and separation (e.g., fractional crystallisationand chromatographic means) of such isomeric forms are either known inthe art or are readily obtained by adapting the methods taught herein,or known methods, in a known manner.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms of thereof, forexample, as discussed below.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³.Examples of suitable organic cations include, but are n6t limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR⁴ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic,gluconic, glutamic, gycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the active compound. The term “solvate” is usedherein in the conventional sense to refer to a complex of solute (e.g.,active compound, salt of active compound) and solvent. If the solvent iswater, the solvate may be conveniently referred to as a hydrate, forexample, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in a chemically protected form. The term “chemicallyprotected form” is used herein in the conventional chemical sense andpertains to a compound in which one or more reactive functional groupsare protected from undesirable chemical reactions under specifiedconditions (e.g., pH, temperature, radiation, solvent, and the like). Inpractice, well known chemical methods are employed to reversibly renderunreactive a functional group, which otherwise would be reactive, underspecified conditions. In a chemically protected form, one or morereactive functional groups are in the form of a protected or protectinggroup (also known as a masked or masking group or a blocked or blockinggroup). By protecting a reactive functional group, reactions involvingother unprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley andSons, 1999).

A wide variety of such “protecting,” “blocking,” or “masking” methodsare widely used and well known in organic synthesis. For example, acompound which has two nonequivalent reactive functional groups, both ofwhich would be reactive under specified conditions, may be derivatizedto render one of the functional groups “protected,” and thereforeunreactive, under the specified conditions; so protected, the compoundmay be used as a reactant which has effectively only one reactivefunctional group. After the desired reaction (involving the otherfunctional group) is complete, the protected group may be “deprotected”to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid.

For example, an amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), as a2-(phenylsulphonyl)ethyloxy amide (—NH-Psec); or, in suitable cases(e.g., cyclic amines), as a nitroxide radical (>N—O.).

For example, a carboxylic acid group may be protected as an ester forexample, as: an C₁₋₇alkyl ester (e.g., a methyl ester; a t-butyl ester);a C₁₋₇haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); atriC₁₋₇alkylsilyl—C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇alkyl ester (e.g.,a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as amethyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in the form of a prodrug. The term “prodrug,” as usedherein, pertains to a compound which, when metabolised (e.g., in vivo),yields the desired active compound. Typically, the prodrug is inactive,or less active than the active compound, but may provide advantageoushandling, administration, or metabolic properties.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula—C(═O)OR wherein R is:

C₁₋₇alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C₁₋₇aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl;2-(4-morpholino)ethyl); and

acyloxy-C₁₋₇alkyl (e.g., acyloxymethyl;

acyloxyethyl;

pivaloyloxymethyl;

acetoxymethyl;

1-acetoxyethyl;

1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl;

1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;

1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;

1-cyclohexyl-carbonyloxyethyl;

cyclohexyloxy-carbonyloxymethyl;

1-cyclohexyloxy-carbonyloxyethyl;

(4-tetrahydropyranyloxy)carbonyloxymethyl;

1-(4-tetrahydropyranyloxy)carbonyloxyethyl;

(4-tetrahydropyranyl)carbonyloxymethyl; and

1-(4-tetrahydropyranyl)carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound. For example, the prodrug may be a sugar derivativeor other glycoside conjugate, or may be an amino acid ester derivative.

Acronyms

For convenience, many chemical moieties are represented using well knownabbreviations, including but not limited to, methyl (Me), ethyl (Et),n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), sec-butyl (sBu),iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex),phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy(MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

For convenience, many chemical compounds are represented using wellknown abbreviations, including but not limited to, methanol (MeOH),ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), etheror diethyl ether (Et₂O), acetic acid (AcOH), dichloromethane (methylenechloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA),dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide(DMSO).

Synthesis

Several methods for the chemical synthesis of compounds of the presentinvention are described herein. These methods may be modified and/oradapted in known ways in order to facilitate the synthesis of additionalcompounds within the scope of the present invention.

Method A General Method for the Synthesis of 1-Sulfonyl-1H-Indoles

Treatment of the appropriate 1-unsubstituted-1H-indole with theappropriate sulfonyl chloride compound (R—SO₂Cl), for example, in thepresence of tetrabutylammonium hydrogensulfate (TBAHS), for example, intoluene, and aqueous sodium hydroxide, gives the corresponding1-substituted 1H-indole. An example of such a method is described below.

For example, to a vigorously stirred solution of1-unsubstituted-1H-indole (8.5 mmol) and tetrabutylammoniumhydrogensulfate (TBAHS) (1.28 mmol) in toluene (25 mL) at 0° C. is added50% aqueous sodium hydroxide (25 mL) and sulfonyl chloride compound(12.8 mmol). The resultant solution is stirred at room temperature for16 hours. After this time, the organic layer is separated and washedwith 1N HCl (2×25 mL), saturated aqueous NaHCO₃ (2×25 mL), water (25mL), and brine (25 mL), and is dried over MgSO₄, and is evaporated todryness to yield the desired 1-sulfonyl-1H-indole.

Method B General Method for the Synthesis of4,4-Dimethoxy-Cyclohexa-2,5-Dienones

Treatment of the appropriate 4-methoxyphenol with iodobenzene diacetate,for example, in methanol, under a nitrogen atmosphere, gives thecorresponding 4,4-dimethoxy-cyclohexa-2,5-dienone. An example of such amethod is described below.

For example, a solution of 4-methoxyphenol (40 mmol) and iodobenzenediacetate (14.3 g, 44 mmol) in methanol (150 mL) is stirred at 0° C.,under a nitrogen atmosphere for 15 minutes. The solution is allowed towarm to room temperature and stirring is continued for 30 minutes.Solvent is removed in vacuo to yield the desired product.

Method C General Method for the Synthesis of4-(1-Sulfonyl-1H-Indol-2-yl)-4-(Hydroxy)-Cyclohexa-2,5-Dieneones

Treatment of the appropriate 1-sulfonyl-1H-indoles with n-butyl lithium,followed by the addition of the appropriate4,4-dimethoxy-cyclohexa-2,5-dienone, gives the corresponding4-(1-sulfonyl-1H-indol-2-yl)-4-(hydroxy)-cyclohexa-2,5-dieneone. Anexample of such a method is described below.

For example, to a stirring solution of n-butyl lithium (3.3 mL, 1.6 M inhexanes, 5.2 mmol) in tetrahydrofuran (THF) (7 mL) at −78° C. is added asolution of 1-sulphonyl-1H-indole (3.5 mmol) in THF (7 mL) dropwise,under a nitrogen atmosphere. Following addition, the solution is stirredat −78° C. for 1.5 hours. After this time, the resultant solution isadded via cannular to a stirring solution of freshly prepared4,4-dimethoxy-cyclohexa-2,5-dienone (0.54 g, 3.5 mmol) in THF (14 mL) at−78° C. Following addition, the solution is stirred at −78° C. for 2hours. After this time, the resultant solution is poured into brine (25mL) and extracted with CH₂Cl₂ (3×25 mL). The combined organic layer iswashed with water (3×20 mL), brine (2×20 mL), and is dried over MgSO₄,and is filtered and evaporated to dryness. The dark oil is redissolvedin acetone (20 mL) and 10% aqueous acetic acid (20 mL) and heated atreflux for 1 hour. After this time, the solution is allowed to cool toroom temperature and extracted with CH₂Cl₂ (3×25 mL). The combinedorganic layer is washed with water (3×20 mL), brine (2×20 mL), and isdried over MgSO₄, filtered and evaporated to dryness. The product ispurified by flash column chromatography (4:1 hexane:EtOAc) to yield thedesired product.

Method D General Method for the Synthesis of4,4-Dimethoxy-4H-Naphthalen-1-One

Treatment of the appropriate 4-methoxynaphthol with iodobenzenediacetate, for example, in methanol, under a nitrogen atmosphere, givesthe corresponding 4,4-dimethoxy-4H-naphthalen-1-one. An example of sucha method is described below.

For example, a solution of 4-methoxynaphthol (16 mmol) and iodobenzenediacetate (6.1 g, 19 mmol) in methanol (75 mL) is stirred at roomtemperature, under a nitrogen atmosphere for 1 hour. The resultant darkblue solution is poured into a saturated solution of NaHCO₃ (75 mL),then evaporated to reduced volume. The blue oil is extracted with CH₂Cl₂(3×75 mL) and the organic layer is washed with water (3×75 mL), brine(2×75 mL), and is dried over MgSO₄, and filtered and evaporated todryness (bath temp. <40° C.) to yield the product as a dark bluesemi-solid.

Method E General Method for the Synthesis of4-(1-Sulfonyl-1H-Indol-2-yl)-4-(Hydroxy)-Cyclohexa-2,5-Dieneones

Treatment of the appropriate 1-sulfonyl-1H-indoles with n-butyl lithium,followed by the addition of the appropriate4,4-dimethoxy-4H-naphthalen-1-one, gives the corresponding4-(1-sulfonyl-1H-indol-2-yl)-4-(hydroxy)-4H-naphthalen-1-one. An exampleof such a method is described below.

For example, to a stirring solution of n-butyl lithium (3.3 mL, 1.6 M inhexanes, 5.2 mmol) in THF (7 mL) at −78° C. is added a solution of1-sulphonyl-1H-indole (3.5 mmol) in THF (7 mL) dropwise, under anitrogen atmosphere. Following addition, the solution is stirred at −78°C. for 1.5 hours. After this time, the resultant solution is added viacannular to a stirring solution of freshly prepared4,4-dimethoxy-4H-naphthalen-1-one (3.5 mmol) in THF (14 mL) at −78° C.Following addition, the solution is stirred at −78° C. for 2 hours.After this time, the resultant solution is poured into brine (25 mL) andextracted with CH₂Cl₂ (3×25 mL). The combined organic layer is washedwith water (3×20 mL), brine (2×20 mL), and dried over MgSO₄, andfiltered and evaporated to dryness. The dark oil is redissolved inacetone (20 mL) and 10% aqueous acetic acid (20 mL) and heated at refluxfor 1 hour. After this time, the solution is allowed to cool to roomtemperature and extracted with CH₂Cl₂ (3×25 mL). The combined organiclayer is washed with water (3×20 mL), brine (2×20 mL), and dried overMgSO₄, and filtered and evaporated to dryness. The product is purifiedby flash column chromatography (4:1 hexane: EtOAc) to yield the desiredproduct.

Method F General Method for Preparation of Substituted ArylsulfonylChlorides

Appropriate substituted arylsulfonyl chlorides, sutiable for use in theabove methods, may be prepared, for example, by reaction of theappropriate substituted aromatic compound with chlorosulfonic acid. Anexample of such a method is described below.

Method G General Method for Preparation of Oxy-Substituted Compounds

Oxy-substituted-sulfonyl compounds may be prepared from thecorresponding methoxy compound. For example, the methoxy compound may bedemethylated, e.g., with boron tribromide in methylene chloride, and theresulting hydroxy compound may be reacted with a suitable alkyl halidecompound, including substituted alkyl halides, such as iodoacetic acid,to give the corresponding oxy-substituted-sulfonyl compound. An exampleof such a method is described below.

Method H General Method for Preparation of Amino-Substituted Compounds

Amino-substituted-sulfonyl compounds may be prepared from thecorresponding acetyl-amino compound, which may itself be prepared fromcommercially available acetylaminobenzene sulfonylchloride, usingmethods described above. For example, the acetyl-amino compound mayconverted to the free amino, e.g., by hydrolysis with hot dilute HCl,and the resulting hydroxy compound may be reacted with a suitable alkylhalide compound, including substituted alkyl halides, such as aminoalkyliodide, to give the corresponding amino-substituted-sulfonyl compound.An example of such a method is described below.

Method I General Method for the Synthesis of bis-thiol Adducts

Treatment of the appropriate 1-sulfonyl-1H-indol-2-yl-quinol with theappropriate thiol (RSH), for example in ethanol in the presence oftriethylamine, gives the corresponding di-thiol adduct. An example ofsuch a method is described below.

To a solution of the quinol (0.1 g) in ethanol (5 mL) is added the thiol(2.0 equivalents) followed by triethylamine (0.1 equivalents). After twohours the solvent is removed under vacuum and the residue stirred withdiethylether:hexane (1:1, 5 mL). The precipitate is collected on afilter and dried under vacuum.

Method J General Method for the Synthesis of mono-thiol Adducts

Treatment of the appropriate 1-sulfonyl-1H-indol-2-yl-quinol with theappropriate thiol (RSH), for example in ethanol, gives the correspondingmono-thiol adduct. An example of such a method is described below.

To a solution of the quinol (0.1 g) in ethanol (5 mL) was added thethiol (2.0 equivalents). After two hours the solvent was removed undervacuum and the residue dissolved in diethylether (1 mL) and purified bycolumn chromatography (silica gel, EtOAc:hexane 2:8).

Uses

The present invention provides active compounds, specifically, activeantiproliferative agents, anticancer agents, and/orthioredoxin/thioredoxin reductase inhibitors.

The term “active,” as used herein, pertains to compounds which arecapable of, e.g., inhibiting cell proliferation, treating cancer,inhibiting thioredoxin/thioredoxin reductase, and specifically includesboth compounds with intrinsic activity (drugs) as well as prodrugs ofsuch compounds, which prodrugs may themselves exhibit little or nointrinsic activity.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound is active. For example, assays which mayconveniently be used in order to assess the activity offered by aparticular compound are described in the examples below.

Antiproliferative Applications

The present invention also provides active compounds which (a) regulate(e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression;(c) promote apoptosis; or (d) a combination of one or more of these.

Thus, the present invention also provides methods of (a) regulating(e.g., inhibiting) cell proliferation; (b) inhibiting cell cycleprogression; (c) promoting apoptosis; or (d) a combination of one ormore of these, in vitro or in vivo, comprising contacting a cell with(e.g., exposing a cell to) an effective amount of an active compound, asdescribed herein.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound regulate (e.g., inhibit) cell proliferation,etc. For example, assays which may conveniently be used to assess theactivity offered by a particular compound are described in the examplesbelow.

For example, a sample of cells (e.g., from a tumour) may be grown invitro and an active compound brought into contact with said cells, andthe effect of the compound on those cells observed. As an example of“effect,” the morphological status of the cells (e.g., alive or dead,etc.) may be determined. Where the active compound is found to exert aninfluence on the cells, this may be used as a prognostic or diagnosticmarker of the efficacy of the compound in methods of treating a patientcarrying cells of the same cellular type.

The present invention further provides antiproliferative agents. Theterm “antiproliferative agent” as used herein, pertains to a compoundwhich treats a proliferative condition (i.e., a compound which is usefulin the treatment of a proliferative condition).

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a proliferative condition for anyparticular cell type. For example, assays which may conveniently be usedto assess the activity offered by a particular compound are described inthe examples below.

The terms “cell proliferation,” “proliferative condition,”“proliferative disorder,” and “proliferative disease,” are usedinterchangeably herein and pertain to an unwanted or uncontrolledcellular proliferation of excessive or abnormal cells which isundesired, such as, neoplastic or hyperplastic growth, whether in vitroor in vivo.

Examples of proliferative conditions include, but are not limited to,benign, pre-malignant, and malignant cellular proliferation, includingbut not limited to, neoplasms and tumours (e.g., histocytoma, glioma,astrocyoma, osteoma), cancers (e.g., lung cancer, small cell lungcancer, gastrointestinal cancer, bowel cancer, colon cancer, breastcarcinoma, ovarian carcinoma, prostate cancer, testicular cancer, livercancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer,sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias,psoriasis, bone diseases, fibroproliferative disorders (e.g., ofconnective tissues), and atherosclerosis.

In one embodiment, the proliferative condition is colon cancer or renalcancer.

In one embodiment, the proliferative condition is colon cancer.

In one embodiment, the proliferative condition is renal cancer.

In one embodiment, the proliferative condition is melanoma.

Any type of cell may be treated, including but not limited to, lung,gastrointestinal (including, e.g., bowel, colon), breast (mammary),ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas,brain, and skin.

In one embodiment, the cell is a colon cell (e.g., colon tumour cell,colon cancer cell) or a renal cell (e.g., renal tumour cell, renalcancer cell).

In one embodiment, the cell is a colon cell (e.g., colon tumour cell,colon cancer cell).

In one embodiment, the cell is a renal cell (e.g., renal tumour cell,renal cancer cell).

In one embodiment, the cell is a melanoma cell.

Anticancer Applications

Antiproliferative compounds of the present invention have application inthe treatment of cancer, and so the present invention further providesanticancer agents.

The term “anticancer agent” as used herein, pertains to a compound whichtreats a cancer (i.e., a compound which is useful in the treatment of acancer).

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a cancerous condition for any particularcell type. For example, assays which may conveniently be used to assessthe activity offered by a particular compound are described in theexamples below.

The anti-cancer effect may arise through one or more mechanisms,including but not limited to, the regulation of cell proliferation, theinhibition of cell cycle progression, the inhibition of angiogenesis(the formation of new blood vessels), the inhibition of metastasis (thespread of a tumour from its origin), the inhibition of invasion (thespread of tumour cells into neighbouring normal structures), or thepromotion of apoptosis (programmed cell death).

Thioredoxin/Thioredoxin Reductase Applications

The present invention also provides active compounds which inhibitthioredoxin/thioredoxin reductase activity.

The term “inhibiting thioredoxin/thioredoxin reductase,” as used herein,includes: inhibiting thioredoxin/thioredoxin reductase activity;inhibiting the formation of thioredoxin/thioredoxin reductase complexes;and inhibiting the activity of thioredoxin/thioredoxin reductasecomplexes.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound inhibits thioredoxin/thioredoxin reductaseactivity. For example, one assay which may conveniently be used in orderto assess the thioredoxin/thioredoxin reductase inhibition offered by aparticular compound is described in the examples below.

Thus, the present invention also provides methods of inhibitingthioredoxin/thioredoxin reductase in a cell, comprising contacting saidcell with (e.g., exposing said cell to) an effective amount of an activecompound. Such a method may be practised in vitro or in vivo. In oneembodiment, the method is performed in vitro. In one embodiment, themethod is performed in vivo. Preferably, the active compound is providedin the form of a pharmaceutically acceptable composition.

The present invention also provides active compounds which areanti-thioredoxin/thioredoxin reductase agents, and which treat acondition mediated by thioredoxin/thioredoxin reductase.

The term “a condition mediated by thioredoxin/thioredoxin reductase,” asused herein pertains to a condition in which thioredoxin/thioredoxinreductase and/or the action of thioredoxin/thioredoxin reductase isimportant or necessary, e.g., for the onset, progress, expression, etc.of that condition, or a condition which is known to be treated bythioredoxin/thioredoxin reductase inhibitors.

The thioredoxins are ubiquitous proteins containing a conserved-Trp-Cys-Gly-Pro-Cys-Lys- redox catalytic site. Mammalian thioredoxinfamily members include thioredoxin-1 (Trx1), mitochondrial thioredoxin-2(Trx2), and a larger thioredoxin-like protein, p32^(TrxL). Thioredoxinis reduced by NADPH and thioredoxin reductase and, in turn reducesoxidized cysteine groups on proteins. When thioredoxin levels areelevated there is increased cell growth and resistance to the normalmechanism of programmed cell death. An increase in thioredoxin levelsseen in many human primary cancers compared to normal tissue appears tocontribute to increased cancer cell growth and resistance tochemotherapy. Mechanisms by which thioredoxin increases cell growthinclude an increased supply of reducing equivalents for DNA synthesis,activation of transcription factors that regulate cell growth, and anincrease in the sensitivity of cells to other cytokines and growthfactors. The mechanisms for the inhibition of apoptosis by thioredoxinare just now being elucidated. Because of its role in stimulating cancercell growth and as an inhibitor of apoptosis, thioredoxin offers atarget for the development of drugs to treat and prevent cancer. See,for example, the review article by Powis et al., 2000, and referencescited therein.

Thioredoxin was first described in 1964 as a small redox protein fromEscherichia coli. Mammalian thioredoxin was reported in 1967 as a redoxprotein present in rat Novikoff hepatoma cells. Thioredoxin wassubsequently rediscovered under other names, including: (i) adult T cellleukemia-derived factor (ADF), an interleukin-2 (IL-2) receptor-inducingfactor produced by human T-lymphotrophic virus type 1 (HTLV 1)-infectedT cells; and, (ii) early pregnancy factor, part of a complex in theserum of pregnant animals that increases the complement-dependentinhibition of lymphocyte binding to heterologous blood cells. Theseproteins were shown to be identical when the correct predicted aminoacid sequence of thioredoxin was published, and they are all nowreferred to as thioredoxin (Trx). A truncated form of thioredoxin,eosinophil cytotoxicity enhancing factor, has also been described.

Members of the thioredoxin family of proteins have as a conservedcatalytic site -Trp-Cys-Gly-Pro-Cys-Lys- that undergoes reversibleoxidation to the cysteine-disulfide (Trx-S₂) form through the transferof reducing equivalents to a disulfide substrate (X—S₂). The oxidizedthioredoxin is reduced back to the cysteine-thiol form [Trx-(SH)₂] bythe NADPH-dependent flavoprotein thioredoxin reductase (TR).

Mammalian thioredoxin reductases are homodimeric, flavin adeninedinucleotide-containing proteins with a penultimate C-terminalselenocysteine (SeCys) residue. The conserved redox catalytic site ofthioredoxin reductase, -Cys-Val-Asn-Val-Gly-Cys-, undergoes reversibleoxidation reduction in much the same way as thioredoxin. Althoughselenocysteine is essential for the full activity of mammalianthioredoxin reductases, human thioredoxin can be relatively efficientlyreduced by the nonselenocysteine-containing bacterial thioredoxinreductase. To date, two human thioredoxin reductases have been cloned,TR1, found predominantly in the cytosol, and TR2, which has a putativemitochondrial import sequence.

Two forms of thioredoxin have been cloned, thioredoxin-1 (Trx-1) andthioredoxin 2 (Trx-2). Human Trx-1 is a 104 amino acid protein with amolecular weight of 12 kDa that contains two catalytic site Cys residues-Trp-Cys³²-Gly-Pro-Cys³⁵-Lys- found in all thioredoxin proteins, as wellas three additional Cys residues, Cys⁶², Cys⁶⁹, and Cys⁷³, that are notfound in bacterial thioredoxins. Trx-1's from a number of othermammalian species, including chicken, rat, mouse, and bovine, have beencloned.

Thioredoxin variously acts as a growth factor, and antioxidant, acofactor, as a transcription factor regulator, and as an inhibitor ofapoptosis.

Studies with a variety of human primary tumors have shown thatthioredoxin is overexpressed in the tumor compared to levels in thecorresponding normal tissue. Recent immunohistochemical studies usingparaffin-embedded tissue sections have shown that thioredoxin expressionis increased in more than half of human primary gastric cancers. Thethioredoxin levels showed a highly significant positive correlation(p<0.001) with cell proliferation measured by nuclear proliferationantigen and a highly significant negative correlation (p<0.001) withapoptosis measured by the terminal deoxynucleotidyl transferase assay. Acomparison of 49,000 human gene transcripts in human normal colonepithelium and colorectal cancer by the serial analysis of geneexpression (SAGE) technique revealed 548 differentially expressedtranscripts. Thioredoxin mRNA was increased 2-fold in colon cancer celllines and 4-fold in colon tumors.

Plasma and serum levels of thioredoxin, which in normal individuals arebetween 10 and 80 ng/ml (0.86.6 nM), have been reported to be elevatedalmost 2-fold in patients with hepatocellular carcinoma and to decreasefollowing surgical removal of the tumor. Serum thioredoxin was notelevated in patients with other forms of liver disease such as chronichepatitis or liver cirrhosis.

The growth-stimulating and transforming effects of thioredoxin, togetherwith the finding that it is overexpressed by a number of human primarytumors, raise the possibility that thioredoxin is a factor leading toaggressive tumor growth and poor patient prognosis. Because thioredoxinhas also been shown to inhibit apoptosis caused by a number ofanticancer drugs and to be a cause of resistance to the cytotoxiceffects of some anticancer drugs, it is possible that increasedthioredoxin could be a cause of resistance to chemotherapy. Thesefindings make thioredoxin an attractive target for the development ofdrugs to inhibit cancer cell growth. Several such compounds have beenidentified. They include PX-12 (1-methylhydroxypropyl 2-imidazoloyldisulfide), which was identified as an inhibitor of thioredoxin bindingto the Cys⁷³ residue. The median IC₅₀ for growth inhibition of a varietyof cell lines by PX-12 is 8.1 μM. PX-12 has been shown to have in vivoantitumor activity against human tumor xenografts in scid mice andchemopreventive activity in min (multiple intestinal neoplasia) mice,which have a germline mutation in the APC gene seen in familialadenomatous polyposis. The growth inhibition by compound PX-12 in theNCl 60 human tumor cell line panel was significantly correlated with theexpression of thioredoxin mRNA. Several other inhibitors of thioredoxinhave been identified by the COMPARE program from over 50,000 compoundstested by the National Cancer Institute as having a pattern of cellkilling activity in the 60 human tumor cell line panel similar to PX-12.One of these compounds, NSC-131233(2,5-bis[(dimethylamino)methyl]cyclopentanone) is an irreversibleinhibitor of thioredoxin with a K_(I) of 1.0 μM.

The thioredoxins are a family of small redox proteins whose functionsinclude the regulation of cell growth, programmed cell death, and thedevelopment of the organism. When thioredoxin levels are elevated incells, there is increased cell growth and resistance to normalmechanisms of programmed cell death. An increase in thioredoxin levelsseen in many human primary cancers compared to normal tissue may be acontributing factor leading to increased cancer cell growth andresistance to chemotherapeutic drugs. The mechanism for the increase inthioredoxin in cancer cells remains unknown at this time. Because of itsrole as a stimulator of cell growth and an inhibitor of apoptosis,thioredoxin is a target for the development of drugs to treat and,possibly, prevent cancer.

Methods of Treatment, Etc.

The invention further provides methods of treatment for example, of aproliferative condition, cancer, a condition mediated bythioredoxin/thioredoxin reductase, a condition known to be treated bythioredoxin/thioredoxin reductase inhibitors, or other condition asdescribed herein, comprising administering to a subject in need oftreatment a therapeutically-effective amount of an active compound,preferably in the form of a pharmaceutical composition.

The invention further provides active compounds for use in a method oftreatment of the human or animal body, for example, in the treatment ofa proliferative condition, cancer, a condition mediated bythioredoxin/thioredoxin reductase, a condition known to be treated bythioredoxin/thioredoxin reductase inhibitors, or other condition asdescribed herein.

The invention further provides the use of an active compound for themanufacture of a medicament, for example, for the treatment of aproliferative conditions, cancer, a condition mediated bythioredoxin/thioredoxin reductase, a condition known to be treated bythioredoxin/thioredoxin reductase inhibitors, or other condition asdescribed herein.

Treatment

The term “treatment,” as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,and cure of the condition. Treatment as a prophylactic measure (i.e.,prophylaxis) is also included.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of an active compound, or a material, composition or dosageform comprising an active compound, which is effective for producingsome desired therapeutic effect, commensurate with a reasonable benefitrisk ratio.

The term “treatment” includes combination treatments and therapies, inwhich two or more treatments or therapies are combined, for example,sequentially or simultaneously. Examples of treatments and therapiesinclude, but are not limited to, chemotherapy (the administration ofactive agents, including, e.g., drugs, antibodies (e.g., as inimmunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT,ADEPT, etc.); surgery; radiation therapy; and gene therapy.

For example, in one embodiment, the treatment is combination treatmentemploying a compound as described herein, with cisplatin.

Active compounds may also be used, as described above, in combinationtherapies, that is, in conjunction with other agents, for example,cytotoxic agents.

Additional Uses

Active compounds may also be used as cell culture additives to inhibitthioredoxin/thioredoxin reductase, for example, in order to regulatecell proliferation in vitro.

Active compounds may also be used as part of an in vitro assay, forexample, in order to determine whether a candidate host is likely tobenefit from treatment with the compound in question.

Active compounds may also be used as a standard, for example, in anassay, in order to identify other active compounds, otherantiproliferative agents, anticancer agents, thioredoxin/thioredoxinreductase inhibitors, etc.

Kits

One aspect of the invention pertains to a kit comprising (a) the activeingredient, preferably provided in a suitable container and/or withsuitable packaging; and (b) instructions for use, for example, writteninstructions about how to administer the active compound.

The written instructions may also include a list of indications forwhich the active ingredient is a suitable treatment.

Routes of Administration

The active compound or pharmaceutical composition comprising the activecompound may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or topically (i.e., atthe site of desired action).

Routes of administration include, but are not limited to, oral (e.g, byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrastemal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

The Subject

The subject may be a prokaryote (e.g., bacteria) or a eukaryote (e.g.,protoctista, fungi, plants, animals).

The subject may be an animal, a mammal, a placental mammal, a marsupial(e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), arodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., amouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine(e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine(e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate,simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), anape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject may be any of its forms of development, forexample, a spore, a seed, an egg, a larva, a pupa, or a foetus.

Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical formulation (e.g.,composition, preparation, medicament) comprising at least one activecompound, as defined above, together with one or more otherpharmaceutically acceptable ingredients well known to those skilled inthe art, including, but not limited to, pharmaceutically acceptablecarriers, diluents, excipients, adjuvants, fillers, buffers,preservatives, anti-oxidants, lubricants, stabilisers, solubilisers,surfactants (e.g., wetting agents), masking agents, colouring agents,flavouring agents, and sweetening agents. The formulation may furthercomprise other active agents, for example, other therapeutic orprophylactic agents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one active compound, as definedabove, together with one or more other pharmaceutically acceptableingredients well known to those skilled in the art, e.g., carriers,diluents, excipients, etc. If formulated as discrete units (e.g.,tablets, etc.), each unit contains a predetermined amount (dosage) ofthe active compound.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, ingredients, materials, compositions, dosage forms, etc.,which are, within the scope of sound medical judgment, suitable for usein contact with the tissues of the subject in question (e.g., human)without excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio. Each carrier, diluent, excipient, etc. must also be “acceptable”in the sense of being compatible with the other ingredients of theformulation.

Suitable carriers, diluents, excipients, etc. can be found in standardpharmaceutical texts, for example, Remington's Pharmaceutical Sciences,18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbookof Pharmaceutical Excipients, 2nd edition, 1994.

The formulations may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association theactive compound with a carrier +which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active compound with carriers(e.g., liquid carriers, finely divided solid carrier, etc.), and thenshaping the product, if necessary.

The formulation may be prepared to provide for rapid or slow release;immediate, delayed, timed, or sustained release; or a combinationthereof.

Formulations may suitably be in the form of liquids, solutions (e.g.,aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous),emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups,electuaries, mouthwashes, drops, tablets (including, e.g., coatedtablets), granules, powders, losenges, pastilles, capsules (including,e.g., hard and soft gelatin capsules), cachets, pills, ampoules,boluses, suppositories, pessaries, tinctures, gels, pastes, ointments,creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster,bandage, dressing, or the like which is impregnated with one or moreactive compounds and optionally one or more other pharmaceuticallyacceptable ingredients, including, for example, penetration, permeation,and absorption enhancers. Formulations may also suitably be provided ina the form of a depot or reservoir.

The active compound may be dissolved in, suspended in, or admixed withone or more other pharmaceutically acceptable ingredients. The activecompound may be presented in a liposome or other microparticulate whichis designed to target the active compound, for example, to bloodcomponents or one or more organs.

Formulations suitable for oral administration (e.g, by ingestion)include liquids, solutions (e.g., aqueous, non-aqueous), suspensions(e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water,water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders,capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes,losenges, pastilles, as well as patches, adhesive plasters, depots, andreservoirs. Losenges typically comprise the active compound in aflavored basis, usually sucrose and acacia or tragacanth. Pastillestypically comprise the active compound in an inert matrix, such asgelatin and glycerin, or sucrose and acacia. Mouthwashes typicallycomprise the active compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets,losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),mouthwashes, losenges, pastilles, as well as patches, adhesive plasters,depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),suppositories, pessaries, gels, pastes, ointments, creams, lotions,oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels,pastes, ointments, creams, lotions, and oils, as well as patches,adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression or molding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the active compoundin a free-flowing form such as a powder or granules, optionally mixedwith one or more binders (e.g., povidone, gelatin, acacia, sorbitol,tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g.,lactose, microcrystalline cellulose, calcium hydrogen phosphate);lubricants (e.g., magnesium stearate, talc, silica); disintegrants(e.g., sodium starch glycolate, cross-linked povidone, cross-linkedsodium carboxymethyl cellulose); surface-active or dispersing or wettingagents (e.g., sodium lauryl sulfate); preservatives (e.g., methylp-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours,flavour enhancing agents, and sweeteners. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active compound therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile. Tablets may optionally be provided with acoating, for example, to affect release, for example an enteric coating,to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the active compound and aparaffinic or a water-miscible ointment base.

Creams are typically prepared from the active compound and anoil-in-water cream base. If desired, the aqueous phase of the cream basemay include, for example, at least about 30% w/w of a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active compound through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogues.

Emulsions are typically prepared from the active compound and an oilyphase, which may optionally comprise merely an emulsifier (otherwiseknown as an emulgent), or it may comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabiliser. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabiliser(s) make up the so-called emulsifying wax, and the waxtogether with the oil and/or fat make up the so-called emulsifyingointment base which forms the oily dispersed phase of the creamformulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulphate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the active compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or other mineral oils canbe used.

Formulations suitable for intranasal administration, where the carrieris a liquid, include, for example, nasal spray, nasal drops, or byaerosol administration by nebuliser, include aqueous or oily solutionsof the active compound.

Formulations suitable for intranasal administration, where the carrieris a solid, include, for example, those presented as a coarse powderhaving a particle size, for example, in the range of about 20 to about500 microns which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalationor insufflation therapy) include those presented as an aerosol sprayfrom a pressurised pack, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye dropswherein the active compound is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active compound.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols, for example,cocoa butter or a salicylate; or as a solution or suspension fortreatment by enema.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active compound, such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the activecompound is dissolved, suspended, or otherwise provided (e.g., in aliposome or other microparticulate). Such liquids may additional containother pharmaceutically acceptable ingredients, such as anti-oxidants,buffers, preservatives, stabilisers, bacteriostats, suspending agents,thickening agents, and solutes which render the formulation isotonicwith the blood (or other relevant bodily fluid) of the intendedrecipient. Examples of excipients include, for example, water, alcohols,polyols, glycerol, vegetable oils, and the like. Examples of suitableisotonic carriers for use in such formulations include Sodium ChlorideInjection, Ringer's Solution, or Lactated Ringer's Injection. Typically,the concentration of the active compound in the liquid is from about 1ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1μg/ml. The formulations may be presented in unit-dose or multi-dosesealed containers, for example, ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriatedosages of the active compounds, and compositions comprising the activecompounds, can vary from patient to patient. Determining the optimaldosage will generally involve the balancing of the level of therapeuticbenefit against any risk or deleterious side effects. The selecteddosage level will depend on a variety of factors including, but notlimited to, the activity of the particular compound, the route ofadministration, the time of administration, the rate of excretion of thecompound, the duration of the treatment, other drugs, compounds, and/ormaterials used in combination, the severity of the condition, and thespecies, sex, age, weight, condition, general health, and prior medicalhistory of the patient. The amount of compound and route ofadministration will ultimately be at the discretion of the physician,veterinarian, or clinician, although generally the dosage will beselected to achieve local concentrations at the site of action whichachieve the desired effect without causing substantial harmful ordeleterious side-effects.

Administration can be effected in one dose, continuously orintermittently (e.g., in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell(s) being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician, veterinarian, or clinician.

In general, a suitable dose of the active compound is in the range ofabout 100 μg to about 100 mg per kilogram body weight of the subject perday. Where the active compound is a salt, an ester, an amide, a prodrug,or the like, the amount administered is calculated on the basis of theparent compound and so the actual weight to be used is increasedproportionately.

EXAMPLES

The following are examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

All compounds were characterised by elemental microanalysis (C, H, and Nvalues within 0.4% of theoretical values). Melting points weredetermined using a Gallenkamp melting point apparatus and are reporteduncorrected. ¹H and ¹³C NMR spectra were recorded using a Bruker ARX250spectrometer. IR spectra (as KBr discs) were determined using a Mattson2020 Galaxy series FT-IR spectrophotometer. Mass spectra were recordedon an AEI MS-902 or a VG Micromass 7070E spectrometer. TLC systems forroutine monitoring of reaction mixtures, and for confirming thehomogeneity of analytical samples used Kieselgel 60F₂₅₄ (0.25 mm) silicagel TLC aluminum sheets. Sorbsil silica gel C 60-H (40-60 μm) was usedfor flash chromatographic separations. All reactions were carried outunder inert atmosphere using anhydrous reagents and solvents.Tetrahydrofuran (THF) was dried and purified before use by distillationfrom sodium-benzophenone. All other commerical materials were used asreceived.

Example 1 1-benzenesulfonyl-5-methoxy-1H-indole

The title compound was prepared from benzene sulfonyl chloride and5-methoxy-1H-indole, according to Method A, described above. Yield 67%;mp 73-75° C.; ¹H NMR (CDCl₃) δ 7.55-7.82 (m, 3H), 7.41-7.48 (m, 2H),7.31-7.37 (m, 2H), 6.83-6.90 (m, 2), 6.51-6.52 (dd, J=4 Hz, 1H); ¹³C NMR(CDCl₃) δ 156.9, 138.6, 134.2, 132.2, 129.9, 129.6, 127.5, 127.1, 114.8,114.2, 109.8, 104.1, 56.0; MS (ES⁺) m/z 287.99 (M⁺+1).

Example 2 1-benzenesulfonyl-5-fluoro-1H-indole

The title compound was prepared from benzene sulfonyl chloride and5-fluoro-1H-indole, according to Method A, described above. Yield 73%;¹H NMR (CDCl₃) δ 7.77-7.82 (dd, J=9 Hz, 1H), 7.71-7.74 (m, 2H), 7.47 (d,J=4 Hz, 1H), 7.30-7.45 (m, 3H), 7.03-7.07 (dd, J=9 Hz, 1H), 6.87-6.95(dt, J=9 Hz, 1H), 6.51 (d, J=4 Hz, 1H); MS (AP⁺) m/z 276.0 (M⁺+1), 214.

Example 3 1-(toluene-4-sulfonyl)-1H-indole

The title compound was prepared from toluene-4-sulfonyl chloride and1H-indole, according to Method A, described above. Yield 91%; mp 60-62°C.; ¹H NMR (CDCl₃) δ 8.0-8.03 (dd, J=8 Hz, 1H), 7.78 (d, J=7 Hz, 2H),7.57 (d, J=4 Hz, 1H), 7.52-7.56 (m, 1H), 7.26-7.36 (m, 2H), 7.20-7.23(d, J=8 Hz, 2H), 6.66-6.68 (dd, J=4 Hz, 1H), 2.30 (s, 3H); ¹³C NMR(CDCl₃) δ 145.4, 135.7, 135.3, 131.2, 130.3, 127.2, 126.8, 124.9, 123.7,121.8, 113.9, 109.5, 21.9; MS (ES⁺) m/z 271.93 (M⁺).

Example 4 1-(4-methoxy-benzenesulfonyl)-1H-indole

The title compound was prepared from 4-methoxy-benzene sulfonyl chlorideand 1H-indole, according to Method A, described above. Yield 95%; mp124-126° C.; ¹H NMR (CDCl₃) δ 7.90-7.93 (dd, J=8 Hz, 1H), 7.74 (d, J=9Hz, 2H), 7.43-7.49 (m, 2H), 7.14-7.27 (m, 2H), 6.79 (d, J=9 Hz, 2H),6.56-6.58 (dd, J=4 Hz, 1H), 3.41 (s, 3H); ¹³C NMR (CDCl₃) δ 164.1,135.2, 131.2, 130.1, 129.5, 126.7, 124.9, 123.6, 121.8, 114.8, 113.9,109.3, 56.0; MS (AP⁺) m/z288.05 (M⁺+1).

Example 5 1-(4-fluoro-benzenesulfonyl)-1H-indole

The title compound was prepared from 4-fluoro-benzene sulfonyl chlorideand 1H-indole, according to Method A, described above. Yield 81%; mp135-137° C.; ¹H NMR (CDCl₃) δ 7.86-7.99 (m, 3H), 7.51-7.54 (m, 2H),7.19-7.35 (m, 2H), 7.05-7.12 (m, 2H), 6.66-6.68 (dd, J=4 Hz, 1H); ¹³CNMR (CDCl₃) δ 168.1, 164.0, 135.2, 134.7, 134.6, 131.2, 130.1, 129.9,126.6, 125.2, 123.9, 121.9, 117.2, 116.9, 113.9, 110.0; MS (ES⁺) m/z275.99 (M⁺+1).

Example 6 1-(naphthalene-2-sulfonyl)-1H-indole

The title compound was prepared from naphthalene-2-sulfonyl chloride and1H-indole, according to Method A, described above. Yield 92%; mp103-105° C.; ¹H NMR (CDCl₃) δ 8.33-8.34 (m, 1H), 7.85-7.89 (dd, J=8 Hz,1H), 7.69-7.76 (m, 1H), 7.52-7.64 (m, 3H), 7.29-7.46 (m, 4H), 6.97-7.24(m, 2H), 6.46-6.48 (dd, J=4 Hz, 1H); ¹³C NMR (CDCl₃) δ 135.6, 135.5,135.3, 132.3, 131.2, 130.1, 129.8, 128.9, 128.3, 128.2, 126.8, 125.1,123.8, 121.9, 121.8, 113.9, 109.7; MS (AP⁺) m/z 308.04 (M⁺+1).

Example 7 5-fluoro-1-(toluene-4-sulfonyl)-1H-indole

The title compound was prepared from toluene-4-sulfonyl chloride and5-fluoro-1H-indole, according to Method A, described above. Yield 100%;mp 106-108° C.; ¹H NMR (CDCl₃) δ 8.13-8.19 (dd, J=4, 8 Hz, 1H), 7.96 (d,J=8 Hz, 2H), 7.82 (d, J=4 Hz, 1H), 7.40-7.48 (m, 3H), 7.25-77.38 (m,1H),6.83 (d, J=4 Hz, 1H), 2.55 (s, 3H); ¹³C NMR (CDCl₃) δ 161.9, 158.1,145.6, 135.4, 132.2, 132.1, 131.6, 130.3, 128.5, 127.2, 115.0, 114.9,113.2, 112.8, 109.4, 109.3, 107.5, 107.1, 21.9.

Example 8 1-(2,4,6-Triisopropyl-benzenesulfonyl)-1H-indole

The title compound was prepared from 2,4,6-triisopropyl-benzene sulfonylchloride and 1H-indole, according to Method A, described above. Yield88%; mp 131-133° C.; ¹H NMR (CDCl₃) δ 7.41-7.65 (m, 3H), 7.18-7.28 (m,4H), 6.65-6.68 (dd, J=8 Hz, 1H), 4.15-4.31 (m, 2H), 2.81-2.97 (m, 1H),1.28 and 1.29 (2s, 6H), 0.98-1.12 (m, 12H).

Example 9 4,4-dimethoxy-cyclohexa-2,5-dienone

The title compound was prepared from 4-methoxyphenol, according toMethod B, described above, to give a pale orange oil, which solidifiedat 0° C. Yield 94%; ¹H NMR (CDCl₃) δ 6.8 (d, J=12 Hz, 2H), 6.3 (d, J=12Hz, 2H), 3.33 (s, 6H).

Example 104-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxy-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-benzenesulfonyl-1H-indole (available commercially), according toMethod C, described above. Yield 18%; mp 170-172° C.; ¹H NMR (CDCl₃) δ8.0 (d, J=8 Hz, 1H), 7.87 (d, J=8 Hz, 2H), 7.51-7.60 (m, 3H), 7.30-7.46(m, 3H), 7.18-7.27 (m, 2H), 6.80 (s, 1H), 6.32 (d, J=10 Hz, 2H), 5.50(s, 1H); ¹³C NMR (CDCl₃) δ 185.3, 147.9, 141.2, 138.6, 137.8, 134.7,129.7, 128.7, 128.1, 127.0, 126.6, 125.0, 122.1, 115.6, 114.1, 67.9.

Example 114-(1-benzenesulfonyl-5-methoxy-1H-indol-2-yl)-4-hydroxy-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-benzenesulfonyl-5-methoxy-1H-indole, according to Method C,described above. Yield 32%; mp 126-128° C.; ¹H NMR (CDCl₃) δ 7.73-7.83(m, 3H), 7.40-7.49 (m, 2H), 7.33-7.40 (m, 2H), 6.76-6.84 (m, 3H), 6.64(s, 1H), 6.20 (d, J=10 Hz, 2H), 5.40 (s, 1H), 3.67 (s, 3H); ¹³C NMR(CDCl₃) δ 196.6, 185.3, 157.3, 147.9, 141.8, 137.7, 134.3, 133.2, 129.8,129.7, 129.3, 127.9, 126.9, 116.8, 115.4, 114.4, 104.2, 81.2, 67.9,55.9; MS (AP⁺) m/z 396.09 (M⁺+1), 378.08.

Example 124-(1-benzenesulfonyl-5-fluoro-1H-indol-2-yl)-4-hydroxy-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-benzenesulfonyl-5-fluoro-1H-indole, according to Method C,described above. Yield 21%; mp 166-167° C.; ¹H NMR (CDCl₃) δ 8.03-8.09(m, 1H), 7.94 (d, J=8 Hz, 2H), 7.51-7.70 (m, 5H), 7.12-7.20 (m, 2H),6.86 (s, 1H), 6.42 (d, J=10 Hz, 2H), 5.49 (s, 1H); ¹³C NMR (CDCl₃) δ185.1, 162.4, 158.5, 147.6, 143.0, 137.7, 134.8, 129.9, 129.8, 129.7,128.2, 126.9, 116.9, 116.8, 114.8, 114.4, 113.6, 107.8, 107.4, 67.9; MS(AP⁺) m/z 384.04 (M⁺+1).

Example 134-(hydroxy4-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-(toluene-4-sulfonyl)-1H-indole, according to Method C, describedabove. Yield 12%; mp 159-161° C.; ¹H NMR (CDCl₃) δ 7.90 (d, J=8 Hz, 1H),7.65 (d, J=8 Hz, 2H), 7.48 (d, J=10 Hz, 2H), 7.33 (d, J=7 Hz,1H),6.70-7.25 (m, 4H), 6.70 (s, 1H), 6.23 (d, J=Hz, 2H), 5.55 (s, 1H), 2.25(s, 3H); ¹³C NMR (CDCl₃) δ 185.3, 148.0, 145.9, 141.2, 138.6, 134.9,130.3, 128.7, 127.9, 127.0, 126.5, 124.9, 122.0, 116.6, 115.6, 113.9,67.9, 21.9; MS (AP⁺) m/z 380.04 (M⁺+1).

Example 144-(hydroxy-4-[1-(4-methoxy-benzenesulfonyl)-1H-indol-2-yl]-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-(4-methoxy-benzenesulfonyl)-1H-indole, according to Method C,described above.

Yield 14%; mp 69-71° C.; ¹H NMR (CDCl₃) δ 7.84-7.94 (m,1H), 7.73 (d, J=9Hz, 2H), 7.49 (d, J=10 Hz, 2H), 7.13-7.40 (m, 3H), 6.73-6.86 (m, 2H),6.69 (s, 1H), 6.23 (d, J=10 Hz, 2H), 5.51 (s, 1H), 3.70 (s, 3H); ¹³C NMR(CDCl₃) δ 185.3, 164.4, 149.2, 148.0, 141.1, 140.3, 138.6, 129.6, 129.2,128.8, 126.3, 124.6, 121.9, 115.8, 114.7, 81.9, 72.5, 67.9, 58.1, 56.0,38.8; MS (AP⁺) m/z 396.03 (M⁺+1).

Example 154-[1-(4-fluoro-benzenesulfonyl)-1H-indol-2-yl]-4-hydroxy-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-(4-fluoro-benzenesulfonyl)-1H-indole, according to Method C,described above. Yield 14%; mp 165-166° C.; ¹H NMR (CDCl₃) δ 7.82-7.93(m, 3H), 7.49 (d, J=10 Hz, 2H), 7.35 (d, J=8 Hz, 1H), 7.12-7.28 (m, 2H),6.99-7.05 (m, 2H), 6.73 (s, 1H), 6.25 (d, J=10 Hz, 2H), 5.31 (s, 1H);¹³CNMR (CDCl₃) δ 185.2, 170.9, 170.5, 147.7, 141.0, 138.6, 133.6, 130.1,129.9, 128.8, 128.1, 126.8, 125.2, 122.2, 117.3, 116.9, 115.6, 114.5,69.5, 67.9; MS (AP⁺) m/z 384.04 (M⁺+1).

Example 164-(hydroxy-4-[1-(naphthalene-2-sulfonyl)-1H-indol-2-yl]-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-(naphthalene-2-sulfonyl)-1H-indole, according to Method C,described above. Yield 14%; mp 66-69° C.; ¹H NMR (CDCl₃) δ 8.42 (s,1H),7.96 (d, J=8 Hz, 1H), 7.84 (d, J=7 Hz,1H), 7.64-7.74 (m, 3H),7.49-7.54 (m, 4H), 7.07-7.32 (m, 3H), 6.71 (s, 1H), 6.24 (d, J=10 Hz,2H), 5.50 (s, 1H); ¹³C NMR (CDCl₃) δ 185.4, 150.0, 148.1, 141.3, 138.6,135.7, 134.7, 132.0, 130.3, 130.1, 129.9, 129.3, 128.7, 128.4, 128.3,128.0, 126.6, 124.9, 122.1, 121.3, 116.6, 115.6, 113.9, 68.0; MS (AP⁺)m/z 416.07 (M⁺+1).

Example 174-[5-fluoro-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-4-hydroxy-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-benzenesulfonyl-5-fluoro-1H-indole, according to Method C,described above. Yield 58%; ¹H NMR (CDCl₃) δ 7.85-7.90 (dd, J=4, 9 Hz,1H), 7.65 (d, J=8 Hz, 2H), 7.47 (d, J=10 Hz, 2H), 7.15 (d, J=8 Hz, 2H),6.91-7.02 (m, 2H), 6.66 (s, 1H), 6.25 (d, J=10 Hz, 2H), 5.42 (s, 1H),2.28 (s, 3H); ¹³C NMR (CDCl₃) δ 185.2, 162.3, 158.4, 149.4, 147.8,146.2, 142.9, 134.9, 134.6, 130.4, 129.9, 129.7, 128.6, 128.1, 127.0,116.9, 116.8, 114.7, 114.3, 113.6, 113.5, 107.7, 107.4, 67.9, 22.0.

Example 184-[1-(2,4,6-triisopropyl-benzene-4-sulfonyl)-1H-indol-2-yl]-4-hydroxy-cyclohexa-2,5-dienone

The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienoneand 1-(2,4,6-triisopropyl-benzene-sulfonyl-1H-indole, according toMethod C, described above. Yield 12%; mp 55-57° C.; ¹H NMR (CDCl₃) δ7.37-7.47 (m, 3H), 6.92-7.09 (m, 5H), 6.70 (s, 2H), 6.25 (d, J=10 Hz,2H), 5.41 (s, 1H), 3.73-3.78 (m, 2H), 2.70-2.91 (m, 1H), 1.15 and 1.18(2s, 6H), 0.99-1.01 (m, 12H); ¹³C NMR (CDCl₃) δ 185.5, 155.4, 151.3,148.4, 141.1, 137.8, 132.7, 127.8, 125.6, 124.8, 123.9, 121.9, 113.3,111.1, 68.2, 34.6, 29.7, 24.7, 23.8; MS (AP⁺) m/z 492.21 (M⁺+1).

Example 19 4,4-dimethoxy-4H-naphthalen-1-one

The title compound was prepared from 4-methoxynaphthol, according toMethod D, described above. Yield 98%; ¹H NMR (CDCl₃) δ 8.15 (d, J=8 Hz,1H), 7.4-7.85 (m, 3H), 6.9 (d, J=12 Hz, 1H), 6.55 (d, J=12 Hz, 1H), 3.15(s, 6H).

Example 204-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxy4H-naphthalen-1-one

The title compound was prepared from 4,4-dimethoxy-4H-naphthalen-1-oneand 1-benzenesulfonyl-1H-indole, according to Method E, described above.Yield 20%; mp 175-177° C.; ¹H NMR (CDCl₃) δ 8.19-8.23 (dd, J=7 Hz, 1H),8.02-8.05 (dd, J=9 Hz, 1H), 7.80-7.92 (m, 4H), 7.68-7.73 (t, J=7 Hz,1H), 7.55-7.64 (m, 2H), 7.42-7.48 (t, J=7 Hz, 2H), 7.25-7.32 (m, 3H),7.14-7.20 (m, 1H), 6.37 (d, J=11 Hz, 1H); ¹³C NMR (CDCl₃) δ 189.7,153.9, 149.7, 148.9, 143.7, 143.2, 139.0, 137.9, 135.7, 134.2, 133.7,133.6, 132.4, 131.6, 131.3, 130.8, 129.4, 126.7, 120.5, 74.9; MS (AP⁺)m/z 416.07 (M⁺+1), 398.06.

Example 21 4-hydroxy4-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-4H-naphthalen-1-one

The title compound was prepared from 4,4-dimethoxy-4H-naphthalen-1-oneand 1-(toluene4-sulfonyl)-1H-indole, according to Method E, describedabove. Yield 23%; mp 110-112° C.; ¹H NMR (CDCl₃) δ 8.35-8.39 (dd, J=8Hz, 1H), 8.04 (d, J=8 Hz,1H), 7.74-7.97 (m, 6H), 7.32-7.48 (m, 6H), 6.53(d, J=10 Hz,1H), 2.52 (s, 3H); ¹³C NMR (CDCl₃) δ 189.7, 154.0, 150.2,149.8, 148.8, 143.6, 140.1, 137.9, 135.7, 134.8, 133.6, 132.3, 131.7,131.3, 130.7, 129.3, 126.6, 120.4, 120.3, 74.8, 26.6; MS (AP⁺) m/z430.09 (M⁺+1), 412.14.

Biological Data

Compounds were assessed for their activity using various in vitro and invivo assays, described below.

NCl Screening

Compounds were tested for in vitro activity (48 hour drug exposure)across 60 human cancer cell lines through the National Cancer Institute(NCl) Developmental Therapies Screening Program (Boyd et al., 1995). Themean growth inhibition (GI50) and cytotoxicity lethal concentration(LC₅₀) values are summarized in Table 1. Surprisingly and unexpectedly,many of the compounds had particular activity in colon and renal celllines. TABLE 1 Activity of Compounds In NCI in Vitro 60 Cell Panel meanMean log₁₀ GI₅₀ log₁₀ LC₅₀ Most Senstive Cells Lines Cmpd (μM)^(a)(μM)^(a) mean log₁₀ LC₅₀ (μM)^(a) SIQ-01 −7.41 −5.53 HCT-116: −7.48CAKI-1: −7.28 SIQ-02 −6.87 −5.21 ACHN: −6.35 LOX IMVI: −6.33 SIQ-03−7.18 −5.49 HCT-116: −7.30 LOX IMVI: −7.20 SIQ-04 −6.95 −5.14 HCT-116:−7.32 LOX IMVI: −6.63 SIQ-05 −6.79 −5.20 HCT-116: −6.95 LOX IMVI: −6.42SIQ-06 −6.63 −5.11 HCT-116: −6.44 UO-31: −6.20 SIQ-07 −6.72 −5.25HCT-116: −6.43 U251: −6.29 SIQ-08 ND ND ND ND SIQ-09 −6.37 −4.95HCT-116: −6.26 RXF 393: −6.11 SIQ-10 −6.35 −5.11 HCT-116: −6.10 LOXIMVI: −6.11 SIQ-11 −6.41 −5.25 HCT-116: −6.31 LOX IMVI: −6.14^(a)For definitions of mean GI₅₀ and mean LC₅₀ see Boyd et al., 1995,and Weinstein et al., 1997.ND = not done.Colon: HCT-116.Renal: CAKI-1, ACHN, RXF 393, UO-31.Melanoma: LOX IMVI.CNS Cancer: U251.Growth Inhibitory Assay

Compounds were prepared as 10 mM top stocks, dissolved in DMSO, andstored at 4° C., protected from light, for a maximum period of 4 weeks.Human derived cell lines (HCT 116, HT29 colon carcinoma) were routinelycultivated at 37° C. in an atmosphere of 5% CO₂ in RPMI 1640 mediumsupplemented with 2 mM L-glutamine and 10% fetal calf serum andsubcultured twice weekly to maintain continuous logarithmic growth.Cells were seeded into 96-well microtiter plates at a density of 5×10³per well and allowed 24 hours to adhere before drugs were introduced(final concentration 0.1 nM-100 μM, n=8). Serial drug dilutions wereprepared in medium immediately prior to each assay. At the time of drugaddition and following 72 hour exposure, MTT was added to each well(final concentration 400 g/mL). Incubation at 37° C. for 4 hr allowedreduction of MTT by mitochondrial dehydrogenase to an insoluble formazanproduct. Well contents were aspirated and formazan solubilized byaddition of DMSO:glycine buffer (pH 10.5) (4:1). Absorbance was measuredusing an Anthos Labtec systems plate reader at 550 nm, and used as ameasure of cell viability; thus cell growth or drug toxicity wasdetermined. The results are summarised in Table 2. TABLE 2 In VitroActivity IC50 (μM) Compound HCT 116 HT 29 SIQ-01 BW 114 0.086 0.259SIQ-03 JMB 40.2 0.068 0.347 SIQ-04 JMB 69 0.036 0.206 SIQ-05 JMB 780.203 0.420 SIQ-07 JMB 79 0.193 0.274 SIQ-10 JMB 49 0.205 0.444 SIQ-11JMB 68 0.155 0.391 DMSO — >100 >100Thioredoxin Activity

Assays were performed using methods analogous to those described inKirkpatrick et al., 1999 and Kunkel et al., 1997.

Thioredoxin (TR) (specific activity 43.6 μmol NADPH reduced/min/mgprotein at 21° C.) was purified from human placenta as previouslydescribed (Oblong et al., 1993). Recombinant hTrx was expressed inEscherichia coli and purified as previously described (Gasdaska et al.,1994). The Trx and TR were stored at −20° C. with 5 mM dithiothreitol(DTT) which was removed before use with a desalting column (PDIO,Pharmacla, Uppsala, Sweden).

Microtitre plate colorimetric assays, based on the increase inabsorbance at 405 nm which occurs as dithionitrobenzoic acid (DTNB) isreduced by the enzyme-mediated transfer of reducing equivalents fromNADPH, were used to measure TR/Trx-dependent insulin-reduction and TRactivity (see, e.g., Kunkel et al., 1997).

Thioredoxin reductase/thioredox independent insulin reducing activitywas measured in an incubation with a final volume of 60 μL containing100 mM HEPES buffer, pH 7.2, 5 mM EDTA (HE buffer), 1 mM NADPH, 1.0 μMthioredoxin reductase, 0.8 μM thioredoxin, and 2.5 mg/ml bovine insulinin flat-bottom 96-well microtitre plates. Compounds were diluted in HEbuffer and added to the wells as 20 μL aliquots. Incubations were for 30min at 37° C. The reaction was stopped by the addition of 100 μL of 6 Mguanidine HCl, 50 mM Tris, pH 8.0, and 10 mM DTNB, and the absorbancemeasured at 405 nm.

Assays of TR activity were run in flat-bottom 96-well microtitre platesin a final incubation volume of 60 μL containing HE buffer, 10 mM DTNB,1.0 μM thioredoxin reductase, and 1 mM NADPH. Compounds were diluted inHE buffer and added to the wells as aliquots. To ensure uniform coverageof the bottom of the well, the plate was briefly spun at 3000 g. Tostart the reaction, NADPH and DTNB were added as a 20 μL aliquots in HEbuffer and the plate was moved to the plate reader preheated to 37° C.The optical density at 405 nm was measured every 10 s and initial linearreaction rates were determined. The data are summarised in Table 3.TABLE 3 Inhibition of Thioredoxin/Thioredoxin Reductase(Tx/TR)-catalysed reduction of Insulin IC₅₀ (mM) Mean GI₅₀ CompoundTx/TR TR (μM) SIQ-01 BW 114 0.152 ND 0.152 SIQ-03 JMB 40.2 0.527 ND0.527 SIQ-04 JMB 69 <0.1 ND <0.1 SIQ-11 JMB 68 >1.0 ND >1.0In Vivo Studies

The in vivo activity of SIQ-01 was studied. The maximum tolerated doseof SIQ-01 in mice is 30 mg/kg on a daily (×5) schedule. Combinationtreatment of SIQ-01 and cisplatin was active against the HCT116 coloncarcinoma tumour when administered to tumour-bearing mice (15 mgSIC-01/kg administered by intraperitoneal injection on days 1-5 and8-10; 4 mg cisplatin/kg administered subcutaneously on days 1 and 8),and gave a maximum T/C (Test/Control) of 49%. Treatment with cisplatinalone (same regimen) gave a maximum T/C (Test/Control) of 56%.

Without wishing to be bound to any particular theory, it is believedthat thioredoxin is associated with resistance to cisplatin therapy, andthat combination therapy with both a thioredoxin inhibitor (such as thecompounds described herein) and cisplatin provides improved therapy, ascompared to therapy with cisplatin alone. The in vivo studies describeabove support this position.

The foregoing has described the principles, preferred embodiments, andmodes of operation of the present invention. However, the inventionshould not be construed as limited to the particular embodimentsdiscussed. Instead, the above-described embodiments should be regardedas illustrative rather than restrictive, and it should be appreciatedthat variations may be made in those embodiments by workers skilled inthe art without departing from the scope of the present invention.

REFERENCES

A number of patents and publications are cited above in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Full citations for these references areprovided below. Each of these references is incorporated herein byreference in its entirety into the present disclosure, to the sameextent as if each individual reference was specifically and individuallyindicated to be incorporated by reference.

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1-89. (canceled)
 90. A compound having the following formula:

wherein: Ar is a 1-(sulfonyl)-1H-indol-2-yl group; the group —OR^(O) isindependently: (a) —OH; (b) an ether group; or: (c) an acyloxy group;the bond marked α is independently: (a) a single bond; or: (b) a doublebond; the bond marked β is independently: (a) a single bond; or: (b) adouble bond; each of R², R³, R⁵, and R⁶, is independently a ringsubstituent and is: (a) H; (b) a monovalent monodentate substituent; or:(c) a ring substituent which, together with an adjacent ringsubstituent, and together with the ring atoms to which these ringsubstituents are attached, form a fused ring; and pharmaceuticallyacceptable salts, esters, amides, solvates, hydrates, and protectedforms thereof.
 91. A compound according to claim 90, wherein α isindependently a double bond and β is independently a double bond, andthe compound has the following formula:


92. A compound according to claim 90, wherein α is independently asingle bond and β is independently a single bond and the compound hasthe following formula:


93. A compound according to claim 90, wherein α is independently asingle bond and β is independently a double bond, and the compound hasthe following formula:


94. A compound according to claim 90, wherein said monovalentmonodentate substituent is selected from: hydroxy (—OH); halo; cyano(—CN); carboxy (—COOH); azido; ester; amino, including: C₁₋₇alkyl-amino;amino-C₁₋₇alkyl-amino; C₁₋₇alkyl, including: halo-C₁₋₇alkyl;amino-C₁₋₇alkyl; carboxy-C₁₋₇alkyl; hydroxy-C₁₋₇alkyl;C₅₋₂₀aryl-C₁₋₇alkyl; ether, including: C₁₋₇alkoxy; halo-C₁₋₇alkoxy;amino-C₁₋₇alkoxy; carboxy-C₁₋₇alkoxy; hydroxy-C₁₋₇alkoxy;C₅₋₂₀aryl-C₁₋₇alkoxy; acyl, including: C₁₋₇alkyl-acyl;halo-C₁₋₇alkyl-acyl; amino-C₁₋₇alkyl-acyl; carboxy-C₁₋₇alkyl-acyl;hydroxy-C₁₋₇alkyl-acyl; C₅₋₂₀aryl-C₁₋₇alkyl-acyl; C₅₋₂₀aryl-acyl;C₅₋₂₀aryl; thiol (—SH); and, thioether.
 95. A compound according toclaim 90, wherein said monovalent monodentate substituent is selectedfrom: —OH; —F, —Cl, —Br, —I; —CN; —COOH; —N₃; —COOMe, —COOEt, —COOtBu,—COOPh, —COOCH₂Ph; —NH₂, —NHMe, —NHEt, —NMe₂, —NEt₂; piperidino,morpholino, piperazino, N-methyl-piperazino; —NH(CH₂)_(w)—NH₂,—NH(CH₂)_(w)—NHMe, —NH(CH₂)_(w)—NMe₂, —NH(CH₂)_(w)—NEt₂; -Me, -Et, -nPr,-iPr, -nBu, -iBu, -sBu, -tBu; —CH₂F, —CH₂Cl, —CF₃, —CCl₃, —CF₂CF₃,—CH₂CF₃, —C(CF₃)₃; —(CH₂)_(w)—NH₂, —(CH₂)_(w)—NHMe, —(CH₂)_(w)—NMe₂,—(CH₂)_(w)—NEt₂; —(CH₂)_(w)—COOH; —(CH₂)_(w)—OH; —CH₂Ph; —OMe, —OEt,-OnPr, -OiPr, -OnBu, -OiBu, —OsBu, -OtBu; —OCH₂F, —OCH₂Cl, —OCF₃,—OCCl₃, —OCF₂CF₃, —OCH₂CF₃, —OC(CF₃)₃; —O(CH₂)_(w)—NH₂,—O(CH₂)_(w)—NHMe, —O(CH₂)_(w)—NMe₂, —O(CH₂)_(w)—NEt₂; —O(CH₂)_(w)—COOH;—O(CH₂)_(w)—OH; —OCH₂Ph; —C(═O)Me, —C(═O)Et, —C(═O)-nPr, —C(═O)-iPr,—C(═O)-nBu, —C(═O)-iBu, —C(═O)-sBu, —C(═O)-tBu; —C(═O)CH₂F, —C(═O)CH₂Cl,—C(═O)CF₃, —C(═O)CCl₃, —C(═O)CF₂CF₃, —C(═O)CH₂CF₃, —C(═O)C(CF₃)₃;—C(═O)(CH₂)_(w)—NH₂, —C(═O)(CH₂)_(w)—NHMe, —C(═O)(CH₂)_(w)—NMe₂,—C(═O)(CH₂)_(w)—NEt₂; —C(═O)(CH₂)_(w)—COOH; —C(═O)(CH₂)_(w)—OH;—C(═O)CH₂Ph; -Ph; —SH; —SMe, —SEt, —SnPr, —S-iPr, —S-nBu, —S-iBu,—S-sBu, —S-tBu, —S—CH₂-Ph, —S-Ph; a thioether group derived fromcysteine, homocysteine, glutathione, or a peptide comprising thesequence -Cys-(X)_(y)-Cys-, where X is an amino acid, and y is aninteger from 1 to 6; wherein w is an integer from 1 to
 7. 96. A compoundaccording to claim 90, wherein each of R², R³, R⁵, and R⁶, isindependently a ring substituent and is: (a) H; or: (b) a monovalentmonodentate substituent.
 97. A compound according to claim 91, whereineach of R², R³, R⁵, and R⁶, is independently a ring substituent and is:(a) H; or: (b) a monovalent monodentate substituent.
 98. A compoundaccording to claim 90, wherein R², R³, R⁵ and R⁶ are —H:


99. A compound according to claim 90, wherein R², R³, R⁵ and R⁶ are —H;α is a double bond; and β is a double bond:


100. A compound according to claim 90, wherein (a) R² and R³, togetherwith the ring atoms to which they are attached, form a fused ring; or(b) R⁵ and R⁶, together with the ring atoms to which they are attached,form a fused ring; or (c) or both (a) and (b).
 101. A compound accordingto claim 99, wherein R² and R³ form a fused benzene ring; and β is adouble bond:


102. A compound according to claim 101, wherein R⁵ and R⁶ do not alsoform a fused ring.
 103. A compound according to claim 99, wherein R² andR³ form a fused benzene ring; β is a double bond; and R⁵ and R⁶ are —H:


104. A compound according to claim 99, wherein R² and R³ form a fusedbenzene ring; β is a double bond; R⁵ and R⁶ are —H; and α is a doublebond:


105. A compound according to claim 90, wherein R^(O) is independently:(a) —H; (b) C₁₋₇alkyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl; and isoptionally substituted; or: (c) C₁₋₇alkyl-acyl, C₃₋₂₀heterocyclyl-acyl,or C₅₋₂₀aryl-acyl; and is optionally substituted.
 106. A compoundaccording to claim 104, wherein R^(O) is optionally substituted with onemore of the following groups: hydroxy (—OH); halo; carboxy (—COOH);amino; and, C₅₋₂₀aryl.
 107. A compound according to claim 90, whereinR^(O) is —H.
 108. A compound according to claim 91, wherein R^(O) is —H.109. A compound according to claim 99, wherein R^(O) is —H.
 110. Acompound according to claim 90, wherein Ar is a group of the followingformula:

wherein: R^(SO) is independently a sulfonyl substituent; and each ofR^(3N), R^(4N), R^(5N), R^(6N) , and R^(7N) is independently an indolylsubsitutent.
 111. A compound according to claim 110, wherein R^(SO) isC₁₋₇alkyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl; and is optionallysubstituted.
 112. A compound according to claim 110, wherein R^(SO) isC₅₋₂₀aryl; and is optionally substituted.
 113. A compound according toclaim 99, wherein Ar is a group of the following formula:

wherein: R^(SO) is independently C₅₋₂₀aryl; and is optionallysubstituted; and each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently an indolyl subsitutent.
 114. A compound according to claim104, wherein Ar is a group of the following formula:

wherein: R^(SO) is independently C₅₋₂₀aryl; and is optionallysubstituted; and each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently an indolyl subsitutent.
 115. A compound according to claim109, wherein Ar is a group of the following formula:

wherein: R^(SO) is independently C₅₋₂₀aryl; and is optionallysubstituted; and each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently an indolyl subsitutent.
 116. A compound according to claim110, wherein R^(SO) is phenyl or naphthyl; and is optionallysubstituted.
 117. A compound according to claim 110, wherein R^(SO) isnaphthyl; and is optionally substituted.
 118. A compound according toclaim 110, wherein R^(SO) is phenyl; and is optionally substituted. 119.A compound according to claim 110, wherein R^(SO) is selected from:

wherein p is an integer from 0 to 5, and each R^(P) is a phenylsubstituent; and

wherein q is an integer from 0 to 3; r is an integer from 0 to 4; andeach R^(P) is a naphthyl substituent.
 120. A compound according to claim119, wherein each R^(P) is independently selected from: hydroxy (—OH);halo; cyano (—CN); carboxy (—COOH); azido; ester; amino, including:amino-C₁₋₇alkyl-amino; C₁₋₇alkyl, including: halo-C₁₋₇alkyl;amino-C₁₋₇alkyl; carboxy-C₁₋₇alkyl; hydroxy-C₁₋₇alkyl;C₅₋₂₀aryl-C₁₋₇alkyl; ether, including: C₁₋₇alkoxy; halo-C₁₋₇alkoxy;amino-C₁₋₇alkoxy; carboxy-C₁₋₇alkoxy; hydroxy-C₁₋₇alkoxy;C₅₋₂₀aryl-C₁₋₇alkoxy; acyl, including: C₁₋₇alkyl-acyl;halo-C₁₋₇alkyl-acyl; amino-C₁₋₇alkyl-acyl; carboxy-C₁₋₇alkyl-acyl;hydroxy-C₁₋₇alkyl-acyl; C₅₋₂₀aryl-C₁₋₇alkyl-acyl; C₅₋₂₀aryl-acyl;C₅₋₂₀aryl.
 121. A compound according to claim 119, wherein each R^(P) isindependently selected from: —OH; —F, —Cl, —Br, —I; —CN; —COOH; —N₃;—COOMe, —COOEt, —COOtBu, —COOPh, —COOCH₂Ph; —NH₂, —NHMe, —NHEt, —NMe₂,—NEt₂; piperidino, morpholino, piperazino, N-methyl-piperazino;—NH(CH₂)_(w)—NH₂, —NH(CH₂)_(w)—NHMe, —NH(CH₂)_(w)—NMe₂,—NH(CH₂)_(w)—NEt₂; -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu; —CH₂F,—CH₂Cl, —CF₃, —CCl₃, —CF₂CF₃, —CH₂CF₃, —C(CF₃)₃; —(CH₂)_(w)—NH₂,—(CH₂)_(w)—NHMe, —(CH₂)_(w)—NMe₂, —(CH₂)_(w)—NEt₂; —(CH₂)_(w)—COOH;—(CH₂)_(w)—OH; —CH₂Ph; —OMe, —OEt, -OnPr, -OiPr, -OnBu, -OiBu, —OsBu,-OtBu; —OCH₂F, —OCH₂Cl, —OCF₃, —OCCl₃, —OCF₂CF₃, —OCH₂CF₃, —OC(CF₃)₃;—O(CH₂)_(w)—NH₂, —O(CH₂)_(w)—NHMe, —O(CH₂)_(w)—NMe₂, —O(CH₂)_(w)—NEt₂;—O(CH₂)_(w)—COOH; —O(CH₂)_(w)—OH; —OCH₂Ph; —C(═O)Me, —C(═O)Et,—C(═O)-nPr, —C(═O)-iPr, —C(═O)-nBu, —C(═O)-iBu, —C(═O)-sBu, —C(═O)-tBu;—C(═O)CH₂F, —C(═O)CH₂Cl, —C(═O)CF₃, —C(═O)CCl₃, —C(═O)CF₂CF₃,—C(═O)CH₂CF₃, —C(═O)C(CF₃)₃; —C(═O)(CH₂)_(w)—NH₂, —C(═O)(CH₂)_(w)—NHMe,—C(═O)(CH₂)_(w)—NMe₂, —C(═O)(CH₂)_(w)—NEt₂; —C(═O)(CH₂)_(w)—COOH;—C(═O)(CH₂)_(w)—OH; —C(═O)CH₂Ph; -Ph; wherein w is an integer from 1 to7.
 122. A compound according to claim 119, wherein each R^(P) isindependently selected from: —F, —Cl, —Br, —I, -Me, -Et, —OMe, —OEt.123. A compound according to claim 119, wherein each R^(P) isindependently selected from: —F, -Me, —OMe.
 124. A compound according toclaim 120, wherein each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently —H, or as defined for R^(P).
 125. A compound according toclaim 120, wherein each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) isindependently selected from: —H, —F, —Cl, —Br, —I, -Me, -Et, —OMe, —OEt.126. A compound according to claim 120, wherein each of R^(3N), R^(4N),R^(6N), and R^(7N) is —H.
 127. A compound selected from compounds havingthe following formulae and pharmaceutically acceptable salts, esters,amides, solvates, hydrates, and protected forms thereof:

wherein R^(O) is —H; wherein Ar is a group of the following formula:

wherein: R^(SO) is selected from:

wherein p is an integer from 0 to 5, and each R^(P) is a phenylsubstituent; and

wherein q is an integer from 0 to 3; r is an integer from 0 to 4; andeach R^(P) is a naphthyl substituent; and wherein: each of R^(3N),R^(4N), R^(5N), R^(6N), and R^(7N) is independently an indolylsubsitutent.
 128. A compound according to claim 127, wherein: each R^(P)is independently selected from: —F —Cl, —Br, —I, -Me, -Et, —OMe, —OEt;and each of R^(3N), R^(4N), R^(5N), R^(6N), and R^(7N) is independentlyselected from: —H, —F, —Cl, —Br, —I, -Me, -Et, —OMe, —OEt.
 129. Acompound selected from the following compounds and pharmaceuticallyacceptable salts, esters, amides, solvates, hydrates, and protectedforms thereof:


130. A composition comprising a compound according to claim 90 and apharmaceutically acceptable carrier or diluent.
 131. A method for thetreatment of a proliferative condition comprising administering to asubject suffering from said condition a therapeutically-effective amountof a compound according to claim
 90. 132. A method for the treatment ofcancer comprising administering to a subject suffering from said cancera therapeutically-effective amount of a compound according to claim 90.133. A method for the treatment of colon cancer or renal cancercomprising administering to a subject suffering from said cancer atherapeutically-effective amount of a compound according to claim 90.134. A method for the treatment of a condition mediated bythioredoxin/thioredoxin reductase comprising administering to a subjectsuffering from said condition a therapeutically-effective amount of acompound according to claim
 90. 135. A method of inhibitingthioredoxin/thioredoxin reductase in a cell, in vitro or in vivo,comprising contacting said cell with an effective amount of according toclaim
 90. 136. A method of regulating cell proliferation, in vitro or invivo, comprising contacting a cell with an effective amount of acompound according to claim
 90. 137. A method of (a) inhibiting cellproliferation; (b) inhibiting cell cycle progression; (c) promotingapoptosis; or (d) a combination of one or more of these, in vitro or invivo, comprising contacting a cell with an effective amount of acompound according to claim 90.